Aryl piperidines as monoacylglycerol lipase modulators

ABSTRACT

Aryl piperidine compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, bipolar disorder), cancers and eye conditions: 
     
       
         
         
             
             
         
       
     
     wherein X, R 2a , R 2b , R 3 , R 4 , R 5a  and R 5b  are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application No.63/000,282, filed on Mar. 26, 2020, which is incorporated herein in itsentirety.

FIELD OF THE INVENTION

The present invention is related to certain aryl piperidine chemicalentities having MGL modulating properties, pharmaceutical compositionscomprising these chemical entities, chemical processes for preparingthese chemical entities and their use in the treatment of diseases,disorders or conditions associated with MGL receptor activity insubjects, in particular humans.

BACKGROUND OF THE INVENTION

Cannabis Sativa and analogs of Δ⁹-tetrahydrocannabinol have been usedsince the days of folk medicine for therapeutic purposes. Theendocannabinoid system consists of two G-protein coupled receptors,cannabinoid receptor type 1 (CB1) (Matsuda et al., Nature, 1990, 346,561-4) and cannabinoid receptor type 2 (CB2) (Munro et al., Nature,1993, 365, 61-5). CB1 receptor is one of the most abundant G-proteincoupled receptor expressed in the brain (Herkenam et al., Proc. Nat.Acad. Sci., 1990, 87 (5), 1932-1936). CB1 is also expressed peripherallyin the liver, gastrointestinal tract, pancreas, adipose tissue, andskeletal muscles (Di Marzo et al., Curr Opin Lipidol, 2007, 18,129-140). CB2 is predominantly expressed in immune cells such asmonocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134) andunder certain conditions (inflammation) in the brain ((Benito et al.,Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al.,Biochem Biophys Res Commun, 2007, 364, 105-110) and cardiac muscles(Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252).

In 1992, N-arachidonoylethanolamine (AEA or anandamide) was found to bean endogenous ligand for cannabinoid receptors (Devane et al., Science,1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) was alsoidentified as an additional endogenous ligand for the cannabinoidreceptors (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiuraet al., Biochem Biophys Res Commun, 1995, 215, 89-97). Concentrations of2-AG were reported to be at least 100 times higher than these ofanandamide in the rat brain (Buczynski and Parsons, Brit J Pharmacol,2010, 160 (3), 423-42). Therefore 2-AG may play more essentialphysiological roles than anandamide in the brain endocannabinoid system(Sugiura et al. Prostaglandins Leukot Essent Fatty Acids., 2002,February-March, 66(2-3):173-92). The endocannabinoid 2-AG is a fullagonist for CB1 and CB2 receptors, while anandamide is a partial agonistfor both receptors (Suguira et al., Prog Lipid Res, 2006, 45(5):405-46).Unlike many classical neurotransmitters, endocannabinoids signal througha retrograde mechanism. They are synthesized on demand in postsynapticneurons and then rapidly degraded following binding to presynapticcannabinoid receptors (Ahn et al., Chem Rev. 2008, 108(5):1687-707).Monoacylglycerol lipase (MGLL, also known as MAG lipase and MGL) is theserine hydrolase responsible for the degradation of 2-AG intoarachidonic acid and glycerol in the central nervous system (Mechoulamet al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., BiochemBiophys Res Commun, 1995, 215, 89-97; Long et al., Nat Chem Biol. 2009January; 5(1):37-44;), Schlosburg et al, Nat Neurosci., 2010, September;13(9):1113-9) and peripheral tissues (Long et al., Chem Biol., 2009 Jul.31; 16(7):744-53). Anandamide is hydrolyzed by fatty acid amidehydrolase (FAAH) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). MGLexists in both soluble and membrane bound forms (Dinh et al., Proc NatlAcad Sci USA., 2002, Aug. 6; 99(16):10819-24). In the brain MGL islocated in presynaptic neurons (Straiker et al., Mol Pharmacol., 2009,December; 76(6):1220-7) and astrocytes (Walter et al., J Neurosci.,2004, Sep. 15; 24(37):8068-74) within regions associated with high CB1receptor density. Compared to wild-type controls, genetic ablation ofMGL expression produces 10-fold increase in brain 2-AG levels withoutaffecting anandamide concentration (Schlosburg et al., Nat Neurosci.,2010, September; 13(9):1113-9).

Thus, MGL modulation offers an interesting strategy for potentiating thecannabinoid system. The primary advantage of this approach is that onlybrain regions where endocannabinoids are actively produced will bemodulated, potentially minimizing the side effects associated withexogenous CB1 agonists. Pharmacological inactivation of MGL by covalentinhibitors in animals increase 2-AG content in brain and peripheraltissues and has been found to produce antinociceptive, anxiolytic andanti-inflammatory effects that are dependent on CB1 and/or CB2 receptors(Long et al., Nat Chem Biol., 2009, January, 5(1):37-44; Ghosh et al.,Life Sci., 2013, Mar. 19, 92(8-9):498-505; Bedse et al., BiolPsychiatry., 2017, Oct. 1, 82(7):488-499; Bernal-Chico et al., Glia.,2015, January, 63(1):163-76; Patel et al. Neurosci Biobehav Rev., 2017,May, 76(Pt A):56-66; Betse et al., Transl Psychiatry., 2018, Apr. 26,8(1):92). In addition to the role of MGL in terminating 2-AG signaling,MGL modulation, including MGL inhibition also promotes CB1/2-independenteffects on neuroinflammation (Nomura et al., Science., 2011, Nov. 11;334(6057):809-13). MGL modulation, including MGL inhibition leads toreduction in proinflammatory prostanoid signaling in animal models oftraumatic brain injury (Katz et al., J Neurotrauma., 2015, Mar. 1;32(5):297-306; Zhang et al., J Cereb Blood Flow Metab., 2015, Mar. 31;35(4): 443-453), neurodegeneration including Alzheimer's disease (Piroet al., Cell Rep., 2012, Jun. 28, 1(6):617-23; Wenzel et al., Life Sci.,2018, Aug. 15, 207:314-322; Chen et al., Cell Rep., 2012, Nov. 29,2(5):1329-39), Parkinson's disease (Nomura et al., Science, 2011, Nov.11, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., 2017,November, 110:14-24), amyotrophic lateral sclerosis (Pasquarelli et al.,Neuropharmacology, 2017, Sep. 15, 124:157-169), multiple sclerosis(Hernadez-Torres et al., Angew Chem Int Ed Engl., 2014, Dec. 8,53(50):13765-70; Bernal-Chico et al., Glia., 2015, January,63(1):163-76), Huntington's disease (Covey et al.,Neuropsychopharmacology, 2018, 43, 2056-2063), Tourette syndrome andstatus epilepticus (Terrone et al., Epilepsia., 2018, January, 59(1),79-91; von Ruden et al., Neurobiol Dis., 2015, May; 77:238-45).

Therefore, by potentiating the cannabinoid system and attenuatingproinflammatory cascades, MGL modulation, including MGL inhibitionoffers a compelling therapeutic approach for the treatment of a vastarray of complex diseases. Importantly, MGL modulation, including MGLinhibition in animals does not produces the full spectrum ofneurobehavioral effects observed with Δ⁹-tetrahydrocannabinol and otherCB1 agonists (Tuo et al., J Med Chem., 2017, Jan. 12, 60(1), 4-46;Mulvihill et al., Life Sci., 2013, Mar. 19, 92(8-9), 492-7).

Endocannabinoid hypoactivity is a risk factor for the treatment ofdepression, anxiety and post-traumatic stress disorders. Millennia ofhuman use of Cannabis sativa, and a brief period in which humans weretreated with the endocannabinoid antagonist, rimonabant, provide supportfor that hypothesis. 2-AG levels are decreased in individuals with majordepression (Hill et al., Pharmacopsychiatry., 2008, March; 41(2): 48-53;Hill et al., Psychoneuroendocrinology., 2009, September; 34(8):1257-1262). Low circulating 2-AG levels predict rates of depression(Hauer et al., Rev Neurosci., 2012, 23(5-6):681-90). Reduced circulating2-AG has been found in patient with post-traumatic stress disorder(PTSD) (Hill et al., Psychoneuroendocrinology, 2013, 38 (12),2952-2961). Healthy volunteers exposed to chronic stressors exhibitedprogressively diminished circulating 2-AG levels which correlated withthe onset of reductions in measures of positive emotions (Yi et al.,Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97). The CB1 receptor inverse agonist/antagonist Rimonabant hasbeen withdrawn from the market due to the high incidence of severedepression and suicidal ideation (Christensen et al., The Lancet, 2007,370, 1706-1713). Therefore, MGL modulators are potentially useful forthe treatment of mood disorders, anxiety, PTSD, autism spectrumdisorders, and Asperger syndrome (Folkes et al., J Clin Invest. 2020;130(4):1728-1742, Jung et al., Nature Communications, 2012, 3, 1080;Wang et al., Mol Psychiatry, 2018 August, 23(8): 1798-1806).

Cannabinoid receptor agonists are clinically used to treat pain,spasticity, emesis, and anorexia (Di Marzo, et al., Annu Rev Med., 2006,57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009, June;13(3):321-31). Therefore, MGL modulators, including MGL inhibitors arealso potentially useful for these indications. MGL exerts CB1-dependantantinociceptive effects in animal models of noxious chemical,inflammatory, thermal and neuropathic pain (Guindon et al., Br JPharmacol., 2011, August; 163(7):1464-78; Kinsey et al., J Pharmacol ExpTher., 2009, September; 330(3):902-10; Long et al., Nat Chem Biol.,2009, January; 5(1):37-44). MGL blockade reduces mechanical and acetoneinduced cold allodynia in mice subjected to chronic constriction injuryof the sciatic nerve (Kinsey et al., J Pharmacol Exp Ther., 2009,September; 330(3):902-10). MGL inhibition produces opiate-sparing eventswith diminished tolerance, constipation, and cannabimimetic side effects(Wilkerson et al., J Pharmacol Exp Ther., 2016, April; 357(1):145-56).MGL blockade is protective in model of inflammatory bowel disease(Alhouayek et al., FASEB J., 2011, August; 25(8):2711-21). MGLinhibition also reverse Paclitaxel-induced nociceptive behavior andproinflammatory markers in a mouse model of chemotherapy-inducedneuropathy (Curry et al., J Pharmacol Exp Ther., 2018, July;366(1):169-18). MGL inhibitors are also potentially useful for thetreatment of chronic inflammatory condition of the urinary bladder likeinterstitial cystitis (Chinnadurai et al., 2019, October; 131: 109321).

Inhibition of 2-AG hydrolysis exerts anti-proliferative activity andreduction in prostate cancer cell invasiveness (Nithipatikom et al.,Cancer Res., 2004, Dec. 15, 64(24):8826-30; Nithipatikom et al., BiochemBiophys Res Commun., 2005, Jul. 15, 332(4):1028-33; Nithipatikom et al.,Prostaglandins Other Lipid Mediat., 2011, February, 94(1-2):34-43). MGLis upregulated in aggressive human cancer cells and primary tumors whereit has a unique role of providing lipolytic sources of free fatty acidsfor synthesis of oncogenic signaling lipids that promote canceraggressiveness. Thus, beyond the physiological roles of MGL in mediatedendocannabinoid signaling, MGL in cancer plays a distinct role inmodulating the fatty acid precursor pools for synthesis ofprotumorigenic signaling lipids in malignant human cancer cells.

MGL blockade shows anti-emetic and anti-nausea effects in a lithiumchloride model of vomiting in shrews (Sticht et al., Br J Pharmacol.,2012, April, 165(8):2425-35).

MGL modulators, including MGL inhibitors may have utility in modulatingdrug dependence of opiates. MGL blockade reduce the intensity ofnaloxone-precipitated morphine withdrawal symptoms in mice. MGL blockadealso attenuated spontaneous withdrawal signs in morphine-dependent mice(Ramesh et al., J Pharmacol Exp Ther., 2011, October, 339(1):173-85).

MGL modulators are also potentially useful for the treatment of eyeconditions, including but not limited to, glaucoma and disease statesarising from elevated intraocular pressure (Miller et al.,Pharmaceuticals, 2018, 11, 50).

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to chemical entities,pharmaceutical compositions containing them, methods of making andpurifying them, and methods for using them the treatment of diseases,disorders, and conditions associated with the MGL modulation.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition associated with the MGL modulation using at least one chemicalentity of the invention.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

Described herein are compounds of Formula (I):

wherein

X is CH₂ or O;

R^(2a) and R^(2b) are each independently selected from H and C₁₋₄alkyl;R³ is selected from:

-   -   (i) phenyl, benzyl, or monocyclic heteroaryl, each optionally        substituted with one, two, or three substituents selected from:        halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkyl-OH, OC₁₋₆alkyl,        OC₁₋₆haloalkyl, SC₁₋₆alkyl, SF₅, Si(CH₃)₃, NR^(a)R^(b),        C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl, phenyl, O-phenyl, and        O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is        optionally substituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl,        or halo groups; or two adjacent ring substituents on the phenyl,        benzyl, or monocyclic heteroaryl, taken together with the atoms        to which they are attached form a fused monocyclic        C₅₋₆cycloalkyl or heterocycloalkyl ring, each ring optionally        substituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl, or halo        groups;        -   wherein R and R^(b) are each independently H or C₁₋₄alkyl;    -   (ii) a bicyclic heteroaryl optionally substituted with C₁₋₄alkyl        or halo; and    -   (iii) C₃₋₆alkyl or C₃₋₆cycloalkyl optionally substituted with        C₁₋₄alkyl, C₁₋₄haloalkyl, or halo;        R⁴ is selected from: H, F, and C₁₋₃alkyl; and        R^(5a) and R^(5b) are each independently selected from H and        CH₃;        and pharmaceutically acceptable salts, isotopes, N-oxides,        solvates, and stereoisomers thereof.

In some embodiments are compounds of Formula (I):

wherein

X is CH₂ or O;

R^(2a) and R^(2b) are each independently selected from H and C₁₋₄alkyl;R³ is selected from:

-   -   (a) phenyl; phenyl substituted with one, two or three members        each independently selected from: halo, C₁₋₆alkyl,        C₁₋₆haloalkyl, C(CH₃)₂OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅,        Si(CH₃)₃, N(CH₃)₂, C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl, phenyl,        O-phenyl, O-pyridyl and C₃₋₆cycloalkyl substituted with CH₃; and    -   (b) pyridyl substituted with C₁₋₆alkyl; naphthyl;

R⁴ is selected from: H, F, and C₁₋₃alkyl; andR^(5a) and R^(5b) are each independently selected from H and CH₃;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “including”, “containing” and “comprising” areused in their open, non-limiting sense.

Unless qualified specifically in particular instances of use, the term“alkyl” refers to a straight- or branched-chain alkyl group having from1 to 8 carbon atoms in the chain. Examples of alkyl groups includemethyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. “C₁₋₆alkyl” refers to straight- orbranched-chain alkyl group having from 1 to 6 carbon atoms in the chain.“C₁₋₄alkyl” refers to straight- or branched-chain alkyl group havingfrom 1 to 4 carbon atoms in the chain. “C₁₋₃alkyl” refers to straight-or branched-chain alkyl group having from 1 to 3 carbon atoms in thechain.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

The term “halogen” or “halo” represents chlorine, fluorine, bromine, oriodine.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 6 carbon atoms in the chain optionally substitutinghydrogens with halogens. The term “C₁₋₆haloalkyl” as used here refers toa straight- or branched-chain alkyl group having from 1 to 6 carbonatoms in the chain, optionally substituting hydrogens with halogens. Theterm “C₁₋₄ haloalkyl” as used here refers to a straight- orbranched-chain alkyl group having from 1 to 4 carbon atoms in the chain,optionally substituting hydrogens with halogens. Examples of “haloalkyl”groups include trifluoromethyl (CF₃), difluoromethyl (CF₂H),monofluoromethyl (CH₂F), pentafluoroethyl (CF₂CF₃), tetrafluoroethyl(CHFCF₃), monofluoroethyl (CH₂CH₂F), trifluoroethyl (CH₂CF₃),tetrafluorotrifluoromethylethyl (CF(CF₃)₂), and groups that in light ofthe ordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples.

The term “aryl” refers to a monocyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) having 6 atoms per ring(Carbon atoms in the aryl groups are sp2 hybridized.)

The term “phenyl” represents the following moiety:

The term “pyridinyl” or “pyridyl” represents the following moiety:

The term “heteroaryl” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising 5 to 14 ring atoms, wherein from 1to 4 of the ring atoms is independently O, N or S and the remaining ringatoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to10 ring atoms. In another embodiment, a heteroaryl group is monocyclicand has 5 or 6 ring atoms. In another embodiment, a heteroaryl group ismonocyclic and has 5 or 6 ring atoms and at least one nitrogen ringatom. A heteroaryl group is joined via a ring carbon atom and anynitrogen atom of a heteroaryl can be optionally oxidized to thecorresponding N-oxide. The term “heteroaryl” also encompasses aheteroaryl group, as defined above, which has been fused to a benzenering.

The term “heterocycloalkyl” as used herein, refers to a ring systemwhich is non-aromatic, 1 to 4 of the ring atoms is independently O, N orS and the remaining ring atoms are carbon atoms, which may optionally befused to another ring (aromatic or heteroaromatic). Non-limitingexamples of illustrative heterocycloalkyl include:

Those skilled in the art will recognize that the species of heteroaryl,heterocyclyloalkyl, cycloalkyl, aryl groups listed or illustrated aboveare not exhaustive, and that additional species within the scope ofthese defined terms may also be selected.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

The term “variable point of attachment” means that a group is allowed tobe attached at more than one alternative position in a structure. Theattachment will always replace a hydrogen atom on one of the ring atoms.In other words, all permutations of bonding are represented by thesingle diagram, as shown in the illustrations below.

Those skilled in the art will recognize that that if more than one suchsubstituent is present for a given ring; the bonding of each substituentis independent of all of the others. The groups listed or illustratedabove are not exhaustive.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of such formula. The compounds of this invention maypossess one or more asymmetric centers; such compounds can therefore beproduced as individual (R)- or (S)-stereoisomers or as mixtures thereof.Thus, any formula given herein is intended to represent a racemate, oneor more of its enantiomeric forms, one or more of its diastereomericforms, and mixtures thereof. Additionally, any formula given herein isintended to refer also to any one of: hydrates, solvates, polymorphs andof such compounds, and mixtures thereof, even if such forms are notlisted explicitly.

The term “R” at a stereocenter designates that the stereocenter ispurely of the R-configuration as defined in the art; likewise, the term“S” means that the stereocenter is purely of the S-configuration. Asused herein, the term “RS” refers to a stereocenter that exists as amixture of the R- and S-configurations.

Compounds containing one stereocenter drawn without a stereo bonddesignation are a mixture of 2 enantiomers. Compounds containing 2stereocenters both drawn without stereo bond designations are a mixtureof 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” anddrawn with stereo bond designations are a 2-component mixture withrelative stereochemistry as drawn. Unlabeled stereocenters drawn withoutstereo bond designations are a mixture of the R- and S-configurations.For unlabeled stereocenters drawn with stereo bond designations, theabsolute stereochemistry is as depicted.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of: for example, R—COOH(s),R—COOH(sol), and R—COO-(sol). In this example, R—COOH(s) refers to thesolid compound, as it could be for example in a tablet or some othersolid pharmaceutical composition or preparation; R—COOH(sol) refers tothe undissociated form of the compound in a solvent; and R—COO-(sol)refers to the dissociated form of the compound in a solvent, such as thedissociated form of the compound in an aqueous environment, whether suchdissociated form derives from R—COOH, from a salt thereof, or from anyother entity that yields R—COO— upon dissociation in the medium beingconsidered. In another example, an expression such as “exposing anentity to compound of formula R—COOH” refers to the exposure of suchentity to the form, or forms, of the compound R—COOH that exists, orexist, in the medium in which such exposure takes place. In stillanother example, an expression such as “reacting an entity with acompound of formula R—COOH” refers to the reacting of (a) such entity inthe chemically relevant form, or forms, of such entity that exists, orexist, in the medium in which such reacting takes place, with (b) thechemically relevant form, or forms, of the compound R—COOH that exists,or exist, in the medium in which such reacting takes place. In thisregard, if such entity is for example in an aqueous environment, it isunderstood that the compound R—COOH is in such same medium, andtherefore the entity is being exposed to species such as R—COOH(aq)and/or R—COO-(aq), where the subscript “(aq)” stands for “aqueous”according to its conventional meaning in chemistry and biochemistry. Acarboxylic acid functional group has been chosen in these nomenclatureexamples; this choice is not intended, however, as a limitation but itis merely an illustration. It is understood that analogous examples canbe provided in terms of other functional groups, including but notlimited to hydroxyl, basic nitrogen members, such as those in amines,and any other group that interacts or transforms according to knownmanners in the medium that contains the compound. Such interactions andtransformations include, but are not limited to, dissociation,association, tautomerism, solvolysis, including hydrolysis, solvation,including hydration, protonation, and deprotonation. No further examplesin this regard are provided herein because these interactions andtransformations in a given medium are known by any one of ordinary skillin the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number in an enriched form. Examples of isotopesthat can be incorporated into compounds of the invention in a form thatexceeds natural abundances include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as²H (or chemical symbol D), ³H (or chemical symbol T), ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Suchisotopically labelled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H,or D) may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventioncan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forsuch variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

The term C_(n-m) alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n.

When the same plurality of substituents is assigned to various groups,the specific individual substituent assignment to each of such groups ismeant to be independently made with respect to the specific individualsubstituent assignments to the remaining groups. By way of illustration,but not as a limitation, if each of groups Q and R can be H or F, thechoice of H or F for Q is made independently of the choice of H or F forR, so the choice of assignment for Q does not determine or condition thechoice of assignment for R, or vice-versa, unless it is expresslyindicated otherwise. Illustrative claim recitation in this regard wouldread as “each of Q and R is independently H or F”, or “each of Q and Ris independently selected from H and F”.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

In another example, a zwitterionic compound would be encompassed hereinby referring to a compound that is known to form a zwitterion, even ifit is not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts, and dipolar ions in the known and well-established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein.

The nomenclature “C_(i)-C_(j)” with j>i, when applied herein to a classof substituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁-C₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

A “pharmaceutically acceptable salt” is intended to mean a salt of anacid or base of a compound represented by Formula (I) that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response.

A compound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

Compounds of Formula (I) may contain at least one nitrogen of basiccharacter, so desired pharmaceutically acceptable salts may be preparedby any suitable method available in the art, for example, treatment ofthe free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, phenylacetic acid, propionic acid, stearic acid, lactic acid,ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid,succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid,lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonicacid, an alpha-hydroxy acid, such as mandelic acid, citric acid, ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoicacid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents.

Compounds of Formula (I) may contain a carboxylic acid moiety, a desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide, alkaline earth metal hydroxide, any compatible mixture ofbases such as those given as examples herein, and any other base andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.Illustrative examples of suitable salts include organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, carbonates,bicarbonates, primary, secondary, and tertiary amines, and cyclicamines, such as benzylamines, pyrrolidines, piperidine, morpholine,piperazine, N-methyl-glucamine and tromethamine and inorganic saltsderived from sodium, calcium, potassium, magnesium, manganese, iron,copper, zinc, aluminum, and lithium.

The compounds of the invention, including their pharmaceuticallyacceptable salts, whether alone or in combination, (collectively,“active agent” or “active agents”) of the present invention are usefulas MGL-modulators in the methods of the invention. Such methods formodulating MGL comprise the use of a therapeutically effective amount ofat least one chemical entity of the invention.

In some embodiments, the MGL modulator is an inhibitor and is used in asubject diagnosed with or suffering from a disease, disorder, orcondition associated with MGL receptor activity, such as those describedherein. Symptoms or disease states are intended to be included withinthe scope of “disease, disorders or conditions.”

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition associated with the MGL receptoractivity. The term “treat” or “treating” as used herein is intended torefer to administration of an active agent or composition of theinvention to a subject for the purpose of effecting a therapeutic orprophylactic benefit through modulation of MGL receptor activity.Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition associated with the MGL modulation. The term“subject” refers to a mammalian patient in need of such treatment, suchas a human.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “MGL inhibitor” is intended to encompass a compound thatinteracts with MGL to substantially reduce or eliminate its catalyticactivity, thereby increasing the concentrations of its substrate(s). Theterm “MGL-modulated” is used to refer to the condition of being affectedby the modulation of the MGL enzyme including the condition of beingaffected by the inhibition of the MGL enzyme. The disclosure is directedto methods for treating, ameliorating and/or preventing diseases,conditions, or disorders associated with pain (including inflammatorypain), and also psychiatric disorders, neurological disorders, cancers,and eye conditions by the administration of therapeutically effectiveamounts of MGL modulators to subjects in need thereof.

The term “modulators” include both inhibitors and activators, where“inhibitors” refer to compounds that decrease, prevent, inactivate,desensitize, or down-regulate the MGL expression or activity, and“activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate MGL expression or activity.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, condition or disorder that is affected byinhibition of MGL) includes a reduction in the frequency and/or severityof one or more symptoms or manifestations of said disease, condition ordisorder; and/or include the prevention of the development of one ormore symptoms or manifestations of said disease, condition or disorderor the development of the disease, condition or disorder.

In treatment methods according to the invention, a therapeuticallyeffective amount of at least one active agent according to the inventionis administered to a subject suffering from or diagnosed as having sucha disease, disorder, or condition. A “therapeutically effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic or prophylactic benefit in subjects in need of suchtreatment for the designated disease, disorder, or condition. Effectiveamounts or doses of the active agents of the present invention may beascertained by routine methods such as modeling, dose escalation studiesor clinical trials, and by taking into consideration routine factors,e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. For a 70-kg human, an illustrative range for asuitable dosage amount is from about 1 to 1000 mg/day in single ormultiple dosage units (e.g., BID, TID, QID or as required by modality).

Once improvement of the subject's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventive or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Subjects may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention are envisaged for use alone,in combination with one or more of other compounds of this invention, orin combination with additional active ingredients in the treatment ofthe conditions discussed below. The additional active ingredients may beco-administered separately with at least one compound of the invention,with active agents of the invention or included with such an agent in apharmaceutical composition according to the invention. In anillustrative embodiment, additional active ingredients are those thatare known or discovered to be effective in the treatment of conditions,disorders, or diseases associated with the MGL modulation, such asanother MGL inhibitor or a compound active against another targetassociated with the particular condition, disorder, or disease. Thecombination may serve to increase efficacy (e.g., by including in thecombination a compound potentiating the potency or effectiveness of anagent according to the invention), decrease one or more side effects, ordecrease the required dose of the active agent according to theinvention.

When referring to inhibiting the target, an “effective amount” means anamount sufficient to affect MGL modulation.

The active agents of the invention are envisaged for use, alone or incombination with one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises a therapeutically effectiveamount of at least one active agent in accordance with the invention.

Pharmaceutically acceptable excipients commonly used in pharmaceuticalcompositions are substances that are non-toxic, biologically tolerable,and otherwise biologically suitable for administration to a subject,such as an inert substance, added to a pharmacological composition orotherwise used as a vehicle, carrier, or diluent to facilitateadministration of an agent and that is compatible therewith. Examples ofsuch excipients include calcium carbonate, calcium phosphate, varioussugars and types of starch, cellulose derivatives, gelatin, vegetableoils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using pharmaceuticallyacceptable excipients and compounding techniques known or that becomeavailable to those of ordinary skill in the art.

The compositions may be administered in the inventive methods by asuitable route of delivery, e.g., oral, parenteral, rectal, topical, orocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. The compositions may be formulated forany one of a plurality of administration routes, such as intravenousinfusion, topical administration, or oral administration. Preferably,the compositions may be formulated for oral administration.

For oral administration, the active agents of the invention can beprovided in the form of tablets or capsules, or as a solution, emulsion,or suspension. To prepare the oral compositions, the active agents maybe formulated to yield a dosage of, e.g., for a 70-kg human, anillustrative range for a suitable dosage amount is from about 1 to 1000mg/day in single or multiple dosage units.

Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent if present,may be magnesium stearate, stearic acid, or talc. If desired, thetablets may be coated with a material such as glyceryl monostearate orglyceryl distearate to delay absorption in the gastrointestinal tract ormay be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin or(hydroxypropyl)methyl cellulose capsules. To prepare hard gelatincapsules, active ingredient(s) may be mixed with a solid, semi-solid, orliquid diluent. Liquids for oral administration may be in the form ofsuspensions, solutions, emulsions, or syrups or may be lyophilized orpresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid compositions may optionallycontain: pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminumstearate gel and the like); non-aqueous vehicles, e.g., oil (forexample, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol, or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, compositions may be formulated for rectaladministration as a suppository, enema, or foam. For parenteral use,including intravenous, intramuscular, intraperitoneal, or subcutaneousroutes, the agents of the invention may be provided in sterile aqueoussolutions or suspensions, buffered to an appropriate pH and isotonicityor in parenterally acceptable oil. Suitable aqueous vehicles includeRinger's solution and isotonic sodium chloride. Such forms may bepresented in unit-dose form such as ampules or disposable injectiondevices, in multi-dose forms such as vials from which the appropriatedose may be withdrawn, or in a solid form or pre-concentrate that can beused to prepare an injectable formulation. Illustrative infusion dosesrange from about 1 to 1000 μg/kg/minute of agent admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.01% to about 20% ofdrug to vehicle, preferably 0.1% to 10%. Another mode of administeringthe agents of the invention may utilize a patch formulation to affecttransdermal delivery.

Active agents may alternatively be administered in methods of thisinvention by inhalation, via the nasal or oral routes, e.g., in a sprayformulation also containing a suitable carrier.

In a further embodiment, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or condition associated with MGL modulation, comprising administering tothe subject in need of such treatment a therapeutically effective amountof the active agent.

The compounds of Formula (I) are useful in methods for treating,ameliorating and/or preventing a disease, a condition or a disorder thatis affected by the inhibition of MGL. Such methods compriseadministering to a subject, including an animal, a mammal, and a humanin need of such treatment, amelioration and/or prevention, atherapeutically effective amount of a compound of Formula (I), or anenantiomer, diastereomer, solvate or pharmaceutically acceptable saltthereof.

In particular, the compounds of Formula (I), or pharmaceuticallyacceptable salts, isotopes, N-oxides, solvates and stereoisomersthereof, are useful for treating, ameliorating and/or preventingdiseases, conditions, or disorders causing pain, psychiatric disorders,neurological disorders, cancers, and eyes conditions. More particularly,the compounds of Formula (I), or pharmaceutically acceptable salts,isotopes, N-oxides, solvates and stereoisomers thereof, are useful fortreating, ameliorating and/or preventing inflammatory pain, majordepressive disorder, treatment resistant depression, anxious depressionor bipolar disorder by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, isotope, N-oxide, solvate orstereoisomer thereof as herein defined.

1) Pain

Examples of inflammatory pain include, but are not limited to, pain dueto a disease, condition, disorder, or a pain state includinginflammatory bowel disease, visceral pain, migraine, post-operativepain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain,joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases,skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomoussnake bite, spider bite, insect sting, neurogenic bladder, interstitialcystitis, urinary tract infection, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, irritable bowel syndrome, cholecystitis, pancreatitis,postmastectomy pain syndrome, menstrual pain, endometriosis, pain due tophysical trauma, headache, sinus headache, tension headache, orarachnoiditis.

One type of inflammatory pain is inflammatoryhyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesiainclude a disease, condition, disorder, or pain state includinginflammation, osteoarthritis, rheumatoid arthritis, back pain, jointpain, abdominal pain, musculoskeletal diseases, skin diseases,post-operative pain, headaches, toothache, burn, sunburn, insect sting,neurogenic bladder, urinary incontinence, interstitial cystitis, urinarytract infection, cough, asthma, chronic obstructive pulmonary disease,rhinitis, contact dermatitis/hypersensitivity and/or dermal allergy,itch, eczema, pharyngitis, enteritis, irritable bowel syndrome,inflammatory bowel diseases including Crohn's Disease, ulcerativecolitis, benign prostatic hypertrophy, and nasal hypersensitivity.

In an embodiment, the present invention is directed to a method fortreating, ameliorating and/or preventing inflammatory visceralhyperalgesia in which an enhanced visceral irritability exists,comprising, consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof. In afurther embodiment, the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

A further embodiment of the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic pain. Examplesof a neuropathic pain include pain due to a disease, condition,disorder, or pain state including cancer, neurological disorders, spineand peripheral nerve surgery, brain tumor, traumatic brain injury (TBI),spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatiguesyndrome, lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia,causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia,supraorbital neuralgia, trigeminal neuralgia, vulvodynia, vidianneuralgia or chemotherapy-induced neuropathy.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic cold allodyniain which a hypersensitivity to a cooling stimuli exists, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

2) Psychiatric Disorders

Examples of psychiatric disorders include, but are not limited to,anxieties such as, social anxiety, post-traumatic stress disorder,phobias, social phobia, special phobias, panic disorder,obsessive-compulsive disorder, acute stress disorder, separation anxietydisorder, and generalized anxiety disorder, as well as depression suchas, major depression, bipolar disorder, seasonal affective disorder,post-natal depression, manic depression, and bipolar depression, mooddisorders and mood affective disorders that can be treated according tothe present invention include, but are not limited to, bipolar disorderI depressed, hypomanic, manic and mixed form; bipolar disorder II;depressive disorders, such as single depressive episode or recurrentmajor depressive disorder, minor depressive disorder,treatment-resistant depression, anxious depression, bipolar disorder,depressive disorder with postpartum onset, depressive disorders withpsychotic symptoms; persistent mood disorders, such as cyclothymia,dysthymia, euthymia; premenstrual dysphoric disorder; psychoses; anddevelopmental disorders such as autism spectrum disorders, and Aspergersyndrome.

3) Neurological Disorders

Examples of neurological disorder include, but are not limited to,tremors, dyskinesias, dystonias, spasticity, Tourette's Syndrome;neuromyelitis optica, Parkinson's disease; Alzheimer's disease; seniledementia; Huntington's disease; Epilepsy/seizure disorders and sleepdisorders.

4) Cancers

Examples of cancers include, but are not limited to, benign skin tumors,prostate tumors, ovarian tumors and cerebral tumors (glioblastomas,medulloepitheliomas, medulloblastomas, neuroblastomas, tumors ofembryonic origin, astrocytomas, astroblastomas, ependymomas,oligodendrogliomas, neuroepitheliomas, epiphyseal tumor,ependymoblastomas, malignant meningiomas, sarcomatosis, malignantmelanomas, schwannomas).

5) Eye Conditions

Examples of eye conditions include, but are not limited to, ocularhypertension, glaucoma, degeneration, and apoptosis of retinal ganglioncells and neuroretinal cells.

Other embodiments of this invention provide for a method for modulatingMGL receptor activity, including when such receptor is in a subject,comprising exposing MGL receptor to a therapeutically effective amountof at least one compound selected from compounds of the invention.

In some embodiments of Formula (I), X is CH₂. In some embodiments, X isO.

In some embodiments, R^(2a) and R^(2b) are each H. In some embodiments,R^(2a) and R^(2b) are each CH₃. In some embodiments, R^(2a) is H andR^(2b) is CH₃.

In some embodiments, R³ is phenyl; or phenyl substituted with one, twoor three members each independently selected from: Cl, F, C₁₋₆alkyl,C₁₋₆haloalkyl, C(CH₃)₂OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, Si(CH₃)₃,SF₅, N(CH₃)₂, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl substituted with CH₃,OC₃₋₆cycloalkyl, phenyl, O-phenyl, and O-pyridyl.

In some embodiments, R³ is phenyl substituted with one, two or threemembers each independently selected from: halo, C₁₋₆alkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅, or Si(CH₃)₃.

In some embodiments, R³ is

In some embodiments, R³ is 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or3-(1-methylcyclopropyl)phenyl.

In some embodiments, R³ is benzyl; tert-butyl; cyclohexyl; phenylsubstituted with 1-methylcyclopropyl or 1-trifluoromethylcyclopropyl, orfused with a cyclobutenyl or cyclohexenyl ring; pyridyl optionallysubstituted with trifluoromethyl, fluoro, or methyl; pyrimidinyloptionally substituted with tert-butyl; or oxazolyl optionallysubstituted with tert-butyl. In some embodiments, R³ is a bicyclicheteroaryl, optionally substituted as described herein. In someembodiments, R³ is phenyl, optionally substituted as described herein.

In some embodiments, R⁴ is H, F, CH₃ or CH₂CH₃. In some embodiments, R⁴is H.

In some embodiments, R^(5a) and R^(5b) are each H. In some embodiments,R^(5a) is CH₃ and R^(5b) is H. In some embodiments, R^(5a) is H andR^(5b) is CH₃.

In some embodiments of Formula (I),

In some embodiments of Formula (I), is

In some embodiments of Formula (I),

In some embodiments of Formula (I),

In some embodiments of Formula (I),

A further embodiment of the current invention is a compound as shownbelow in Table 1.

TABLE 1 Ex # Compound Name 1(2s,4s)-2-(4-(3-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 2(2s,4s)-2-(4-(3-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 3(2s,4s)-2-(4-(2-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 4(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 5(2s,4s)-2-(4-(4-(Difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 6(2s,4s)-2-(4-(3-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 7(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 8(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 9(2s,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 10(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 11(2s,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 12(2s,4s)-2-(4-(4-(Difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 13(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 14(2s,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 15(2s,4s)-2-(4-(3-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 16(2r,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 17(2r,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 18(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 19(2s,4s)-2-(4-(2-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 20(2s,4s)-2-(4-(4-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 21(2s,4s)-2-(4-(3-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 22(2r,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 23(2s,4s)-2-(4-(3-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 24(2s,4s)-2-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 25(2s,4s)-2-(4-(4-Cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 26(2s,4s)-2-(4-(3-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 27(2s,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 28(2s,4s)-2-(4-(4-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 29(2s,4s)-2-(4-(3-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 30(2s,4s)-2-(4-(2,3-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 31(2s,4s)-2-(4-(2,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 32(2r,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 33(2s,4s)-2-(4-(2-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 34(2s,4s)-2-(4-(3,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 35(2s,4s)-2-(4-(2,3-Dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 36(2s,4s)-2-(4-(3-Chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 37(2s,4s)-2-(4-(2-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 38(2s,4s)-2-(4-(3-Isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 39(2r,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 40(2s,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 41(2r,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 42(2s,4s)-2-(4-(1H-Inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 43 (2s,4s)-2-(4-(2,3-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 44(2s,4s)-2-(4-(4-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 45(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 46(2s,4s)-2-(4-(2-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 47(2s,4s)-2-(4-(2,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 48(2s,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 49(2s,4s)-2-(4-(3-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 50(2s,4s)-2-(4-(2-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 51(2r,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;52(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 53(2s,4s)-2-(4-(3-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 54(2s,4s)-2-(4-(4-Chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 55(2s,4s)-2-(4-(2-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 56(2s,4s)-2-(4-(2-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 57(2s,4s)-2-(4-([1,1′-Biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 58(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 59(2s,4s)-2-(4-(4-(Pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 60(2s,4s)-2-(4-(4-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 61(2s,4s)-2-(4-(4-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 62(2s,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 63(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 64(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 65(2s,4s)-2-(4-(4-Cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 66(2s,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 67(2s,4s)-2-(4-(3-(Difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 68(2s,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 69(2r,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 70(2s,4s)-2-(4-(3-Methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 71(2s,4s)-2-(4-(4-(Difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 72(2s,4s)-2-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 73(2r,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 74(2r,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 75(2s,4s)-2-(4-(4-Cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 76(2s,4s)-2-(4-(2-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 77(2s,4s)-2-(4-(3-(Pentafluoro-λ6-sulfaneyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 78(2s,4s)-2-(4-(4-(Pentafluoro-λ6-sulfaneyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 79(2r,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 80(2s,4s)-2-(4-(4-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 81 (racemic)-(2s,4s)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 82(2s,4s)-2-(4-(3-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 83(2s,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 84(2s,4s)-2-(4-(4-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 85(2s,4s)-2-(4-(3,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 86(2s,4s)-2-(4-(2,4-Difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 87(2s,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 88(2s,4s)-2-(4-(4-Fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 89(2s,4s)-2-(4-(2,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 90(2s,4s)-2-(4-(3-Ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 91(2s,4s)-2-(4-(3,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 92(2S*,4s,8R*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 93(2R*,4s,8S*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 94(2s,4s)-2-(4-(3-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 95(2r,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 96(2r,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;97(2s,4s)-2-(4-(4-(tert-Butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 98(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 99(racemic)-(2s,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 100(racemic)-(2r,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 101(2s,4s)-2-(4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 102(2s,4s)-2-[4-(6-Fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8-azaspiro[3.4]octan-7-one; 103(2s,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 104(2s,4s)-2-(4-(Benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 105(2s,4s)-2-(4-(Naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 106(2s,4s)-2-(4-(1H-Indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 107(2s,4s)-2-(4-(4-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 108(2s,4s)-2-(4-(4-(Methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 109(2s,4s)-2-(4-(4-(Dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 110(2s,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 111(2s,4s)-2-(4-Phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;112(2s,4s)-2-(4-(p-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;113(2s,4s)-2-(4-(Naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 114(2s,4s)-2-(4-(4-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 115(2s,4s)-2-(4-(3-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 116(2s,4s)-2-(4-(o-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;117(2s,4s)-2-(4-(4-Ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 118(2s,4s)-2-(4-(3-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 119(2s,4s)-2-(4-(2-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 120(2s,4s)-2-(4-(3-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 121(2s,4s)-2-(4-(4-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 122(2s,4s)-2-(4-(m-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;123 (2s,4s)-2-(4-(4-Methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 124(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 125(2r,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 126(2r,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 127(2r,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 128(2s,4s)-2-(4-Methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 129(2s,4s)-2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 130(2s,4s)-2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 131(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 132(2S*,4s,8R*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 133(2R*,4s,8S*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 134(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one; 135(2s,4s)-2-(4-(4-Chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 136(2s,4s)-2-(4-(Benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 137(2s,4s)-2-(4-Methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 138(2s,4s)-2-(4-Fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 139(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 140(2s,4s)-2-(4-(4-Chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 141(racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] octan-6-one; 142(2s,4S*)-2-((3R*,4R*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 143(2s,4R*)-2-((3S*,4S*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 144(racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 145(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 146(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 147(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 148(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] octan-6-one; 149(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 150(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 151(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 152(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 153(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 154(racemic)-(2s,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)- 7-oxa-5-azaspiro[3.4]octan-6-one; 155(racemic)-(2r,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 156(2s,4R*)-2-((2S*,4R*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 157(2s,4S*)-2-((2R*,4S*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 158(2s,4S*)-2-((2R*,4R*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 159(2s,4R*)-2-((2S*,4S*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] octan-6-one; 160(2s,4S*)-2-((3R*,4R*)-4-([1,r-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 161(2s,4R*)-2-((3S*,4S*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 162(racemic)-(25,47R)-2-((25,45)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 163(2s,4R*)-2-((2S*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 164(2s,4S*)-2-((2R*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 165(2s,4S*)-2-((2R*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 166(2s,4R*)-2-((2S*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 167(2s,4R*)-2-((2S*,4R*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 168(2s,4S*)-2-((2R*,4S*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and 169(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound selectedfrom:

-   (2s,4s)-2-(4-(3-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;-   (2s,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;-   (2s,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;-   (2r,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;    and-   (2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;    and pharmaceutically acceptable salts, isotopes, N-oxides, solvates,    and stereoisomers thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IA):

whereinR³ is selected from:

-   -   (a) phenyl substituted with one or two members each        independently selected from: halo, C₁₋₆alkyl, C₁₋₆haloalkyl,        OC₁₋₆haloalkyl, Si(CH₃)₃, C₃₋₆cycloalkyl, phenyl, O-phenyl, and        C₃₋₆cycloalkyl substituted with CH₃; and

R^(5b) is H or CH₃;or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, orstereoisomer thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IB):

whereinR^(2a) and R^(2b) are each independently selected from H and CH₃;R³ is selected from:

-   -   (a) phenyl; phenyl substituted with one, two or three members        each independently selected from: Cl, F, C₁₋₆alkyl,        C₁₋₆haloalkyl, C(CH₃)₂OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅,        Si(CH₃)₃, N(CH₃)₂, cyclopropyl, cyclobutyl, O-cyclopropyl,        phenyl, O-phenyl, O-pyridyl and

-   -    and    -   (b)

R⁴ is selected from: H, F, CH₃ and CH₂CH₃;R^(5a) is H or CH₃; andR^(5b) is H or CH₃;or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, orstereoisomer thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IC):

wherein

X is CH₂ or O; and

Ring A is selected from:

or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, orstereoisomer thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (ID):

wherein

-   X is CH₂ or O;-   R^(2a) and R^(2b) are each independently selected from H and CH₃;-   R^(b) is selected from: Cl, F, C₁₋₆alkyl, C₁₋₆haloalkyl, C(CH₃)₂OH,    OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅, Si(CH₃)₃, N(CH₃)₂,    cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl, O-phenyl, O-pyridyl    and

-    and-   n is 0, 1, 2, or 3;-   R is selected from: H, F, CH₃ and CH₂CH₃;-   R^(5a) is H or CH₃; and-   R^(5b) is H or CH₃;-   or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or    stereoisomer thereof.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising:

(A) a therapeutically effective amount of at least one compound ofFormula (I) or a pharmaceutically acceptable salt, isotope, N-oxide,solvate, or stereoisomer thereof, and(B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds in Table 1, and pharmaceuticallyacceptable salts, isotopes, N-oxides, solvates, and stereoisomers ofthereof, pharmaceutically acceptable prodrugs of compounds of Table 1,and pharmaceutically active metabolites of compounds of Table 1; and atleast one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from: compounds of Formula (IA), pharmaceuticallyacceptable salts, N-oxides or solvates of compounds of Formula (IA),pharmaceutically acceptable prodrugs of compounds of Formula (IA), andpharmaceutically active metabolites of Formula (IA); and at least onepharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds of Formula (IB), andpharmaceutically acceptable salts, N-oxides or solvates of compounds ofFormula (IB), pharmaceutically acceptable prodrugs of compounds ofFormula (IB), and pharmaceutically active metabolites of Formula (IB);and at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds of Formula (IC), andpharmaceutically acceptable salts, N-oxides or solvates of compounds ofFormula (IC), pharmaceutically acceptable prodrugs of compounds ofFormula (IC), and pharmaceutically active metabolites of Formula (IC);and at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds of Formula (ID), andpharmaceutically acceptable salts, N-oxides or solvates of compounds ofFormula (ID), pharmaceutically acceptable prodrugs of compounds ofFormula (ID), and pharmaceutically active metabolites of Formula (ID);and at least one pharmaceutically acceptable excipient.

Also within the scope of the invention are enantiomers and diastereomersof the compounds of Formula (I) (as well as Formulas (IA), (IB), (IC),and (ID)). Also within the scope of the invention are thepharmaceutically acceptable salts, N-oxides or solvates (includingcombinations thereof) of the compounds of Formula (I) (as well asFormulas (IA), (IB), (IC), and (ID)). Also within the scope of theinvention are the pharmaceutically acceptable prodrugs of compounds ofFormula (I) (as well as Formulas (IA), (IB), (IC), and (ID)), andpharmaceutically active metabolites of the compounds of Formula (I) (aswell as Formulas (IA), (IB), (IC), and (ID)).

Also within the scope of the invention are isotopic variations ofcompounds of Formula (I) (as well as Formulas (IA), (IB), (IC), and(ID)), such as, e.g., deuterated compounds of Formula (I). Also withinthe scope of the invention are the pharmaceutically acceptable salts,N-oxides or solvates (or combinations thereof) of the isotopicvariations of the compounds of Formula (I) (as well as Formulas (IA),(IB), (IC), and (ID)). Also within the scope of the invention are thepharmaceutically acceptable prodrugs of the isotopic variations of thecompounds of Formula (I) (as well as Formulas (IA), (IB), (IC), and(ID)), and pharmaceutically active metabolites of the isotopicvariations of the compounds of Formula (I) (as well as Formulas (IA),(IB), (IC), and (ID)).

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition mediated by MGL receptor activity, comprising administering toa subject in need of such treatment a therapeutically effective amountof at least one compound selected from compounds of Formula (I) andpharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof. Also described herein is the use of a compound ofFormula (I) or a pharmaceutically acceptable salt, isotope, N-oxide,solvate, or stereoisomer thereof in the preparation of a medicament. Insome embodiments, the medicament is for treatment of a disease,disorder, or condition mediated by MGL receptor activity. Also describedherein is a compound of Formula (I), or a pharmaceutically acceptablesalt, isotope, N-oxide, solvate, or stereoisomer thereof, for use in amethod of treating a disease, disorder, or condition mediated by MGLreceptor activity.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition mediated by MGL receptor activity, comprising administering toa subject in need of such treatment a therapeutically effective amountof at least one compound selected from compounds of Formula (I) (as wellas Formulas (IA), (IB), (IC), and (ID)), enantiomers and diastereomersof the compounds of Formula (I) (as well as Formulas (IA), (IB), (IC),and (ID)), isotopic variations of the compounds of Formula (I) (as wellas Formulas (IA), (IB), (IC), and (ID)), and pharmaceutically acceptablesalts of all of the foregoing. Also described herein is the use of acompound of Formula (IA), (IB), (IC), or (ID), or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof inthe preparation of a medicament. In some embodiments, the medicament isfor treatment of a disease, disorder, or condition mediated by MGLreceptor activity. Also described herein is a compound of Formula (IA),(IB), (IC), or (ID), or a pharmaceutically acceptable salt, isotope,N-oxide, solvate, or stereoisomer thereof, for use in a method oftreating a disease, disorder, or condition mediated by MGL receptoractivity.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

TABLE 2 Term Acronym[4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-(Ir[dF(CF₃)ppy]₂(dtbpy))PF₆difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III)hexafluorophosphate Microliter μL Acetonitrile ACN, MeCN Aqueous aqAtmosphere atm tert-Butoxycarbonyl BOC or BocBenzotriazol-1-yloxy-tris(dimethylamino)phosphonium BOPhexafluorophosphate Broad br Cerium (III) chloride CeCl₃ DiatomaceousEarth Celite ® Nickel(II) chloride hexahydrate NiCl₂•6H₂O1,8-Diazabicyclo[5.4.0]undec-7-ene DBU N,N′-Dicyclohexylcarbodiimide DCCMethylene chloride or Dichloromethane DCM Diisobutylaluminum hydrideDIBAL-H N-Ethyldiisopropylamine DIPEA Dimethylacetamide DMA4-(Dimethylamino)pyridine DMAP 1,2-Dimethoxyethane DME DimethylformamideDMF Dess Martin periodinane DMP Dimethyl sulfoxide DMSO1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC, EDAC or EDCIEnantiomeric excess ee Electrospray ionization ESI Diethyl ether Ether,Et₂O Ethyl Acetate EtOAc, or EA Ethanol EtOH Normal-phase silica gelchromatography FCC Grams g Hours h, hr, hrs1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- HATU b]pyridinium3-oxide hexafluorophosphateN,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium HBTUhexafluorophosphate hydroxybenzotriazole HOBt High-pressure liquidchromatography HPLC Hertz Hz Isopropyl alcohol iPrOH, IPA Liquidchromatography and mass spectrometry LCMS Molar M Mass to charge ratiom/z Methanol MeOH Milligrams mg Minute min Milliliter mL Millimoles mmolMass spectrometry MS Normal N Sodium hexamethyldisilazide NaHMDS Sodiumacetate NaOAc n-Butyllithium n-BuLi Nickel(II) chloride ethylene glycoldimethyl ether complex NiCl₂(DME) N-Methyl-2-pyrrolidone NMP Nuclearmagnetic resonance NMR Triflate OTf Pyridinium chlorochromate PCCPalladium on carbon Pd/C Bis(dibenzylideneacetone)palladium Pd(dba)₂[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl₂Palladium (II) acetate Pd(OAc)₂ Palladium-tetrakis(triphenylphosphine)Pd(PPh₃)₄ Triphenylphosphine PPh₃ Parts per million ppm Precipitate pptPolytetrafluoroethylene PTFE Bromotripyrrolidinophosphoniumhexafluorophosphate PyBroP ® Reverse phase RP Retention time R_(t) Roomtemperature rtDicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine RuPhos2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′- RuPhosPd G3 amino-1,1′-biphenyl)]palladium(II) methanesulfonate Saturated satSupercritical Fluid Chromatography SFC Temperature T2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide T3P ®Triethylamine TEA Triethylsilane TES Trifluoroacetic acid TFATrifluoroacetic anhydride TFAA Tetrahydrofuran THF Thin layerchromatography TLC Volume in milliliters of solvent per gram ofsubstrate V, or volumes2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, a compound of formula (V), where R^(a) isC₁₋₄alkyl, is treated with hydroxylamine; using an additive such assodium acetate (NaOAc), and the like; in a suitable solvent such asethanol (EtOH), and the like; to provide a compound of formula (VI). Acompound of formula (VII) is prepared from a compound of formula (VI)using an oxidant such as hydrogen peroxide, urea-hydrogen peroxide, andthe like; in the presence of an activator such as trifluoroaceticanhydride (TFAA), and the like; in the presence of abase such as dibasicsodium phosphate, and the like; in a solvent such as acetonitrile (ACN),and the like.

According to SCHEME 2, compounds of formula (VIIIa) and (VIIIb) areprepared by reacting a compound of formula (VII) with formaldehyde inthe presence of a base such as triethylamine (TEA), and the like; in asolvent such as ACN, and the like. A compound of formula (IX) isprepared by hydrogenolysis of a compound of formula (VIIIb) under anatmosphere of hydrogen gas (H₂) in the presence of a catalyst such aspalladium on carbon (Pd/C), and the like; in a solvent such as ethylacetate (EtOAc), EtOH, and the like. A compound of formula (X) isprepared by the reaction of a compound of formula (IX) with triphosgenein the presence of a base such as TEA, and the like; in a solvent suchas tetrahydrofuran (THF), and the like. A compound of formula (XI),where X is O, is prepared by the acidic deprotection of a compound offormula (X) using an acid such as trifluoroacetic acid (TFA), HCl indioxane, and the like.

According to SCHEME 3, compounds of formula (XIa) and formula (XIb) areprepared by a Michael-type reaction between a compound of formula (VII)and methyl acrylate; in the presence of a base such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like; in a solventsuch as ACN, and the like. Reductive ring closure of a compound offormula (XIa) using a reducing agent such as sodium borohydride (NaBH₄),and the like; an additive such as nickel(II) chloride hexahydrate, andthe like; in a suitable solvent such as methanol (MeOH), and the like;provides a compound of formula (XI), where X is CH₂.

According to SCHEME 4, a compound of formula (XII) is prepared byreacting a compound of formula (VII), where R^(a) is C₁₋₄alkyl; withacetaldehyde in the presence of a base such as TEA, and the like; in asolvent such as ACN, and the like, at temperatures ranging from 0° C. toroom temperature, for a period of 18 h. A compound of formula (XII) issubjected to hydrogenolysis; employing conditions previously described,to provide compounds of formula (XIIIa) and (XIIIb).

According to SCHEME 5, a compound of formula (XIIIa), where R^(a) istert-butyl, is subjected to ring closure conditions with triphosgene,employing conditions previously described, to provide a compound offormula (XIV). A compound of formula (XIV) is subjected to acidicdeprotection conditions previously described to provide a compound offormula (XV), where R^(2a) is H and R^(2b) is CH₃.

According to SCHEME 6, a compound of formula (XVI), is prepared in twosteps from a compound of formula (XIIIa). In a first step, protection acompound of formula (XIIIa), where R^(a) is tert-butyl; is achieved byreaction with di-tert-butyl dicarbonate in the presence of a base suchas TEA, and the like; in a solvent such as dichloromethane (DCM), andthe like. In a second step, oxidation to a ketone compound of formula(XVI) is achieved employing conditions known to one skilled in the art,for example, DMP (Dess-Martin periodinane), SO₃-pyridine, Swernconditions [(COCl)₂, DMSO, Et₃N], PCC, and the like, in a solvent suchas EtOAc, DMSO, DCM, and the like, at temperatures ranging from about−78° C. to room temperature (about 23° C.), to provide a compound offormula (XVI), where PG is BOC, and R^(a) is tert-butyl. In a preferredmethod, oxidation to a compound of formula (XVI) is achieved withDess-Martin periodinane, in DCM, at 20° C. for 4 hours. A compound offormula (XVI) is reacted under conventional Grignard reaction conditionsin the presence of an organo-magnesium halide such as methylmagnesiumbromide, and the like; in in a suitable solvent such as Et20, THF, or amixture thereof, at a temperature ranging from −40° C. to rt; to providea compound of formula (XVII). Deprotection of the BOC protecting groupis achieved according to methodologies known to one skilled in the art.For example, employing acidic conditions such as TFA/DCM, HCl/Dioxane,and the like to provide a compound of formula (XVIII).(2s,4s)-8,8-Dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acidis prepared in two steps from a compound of formula (XVIII). In a firststep, ring closure is achieved employing conditions using triphosgene aspreviously described. Subsequent deprotection of the tert-butyl ester isachieved employing conditions previously described.

According to SCHEME 7, tert-butyl4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate is prepared fromcommercially available or synthetically accessible tert-butyl4-bromopiperidine-1-carboxylate, using an appropriate commerciallyavailable or synthetically accessible bromobenzene such as5-bromo-2-methylphenol; a catalyst such as nickel (II) chloride ethyleneglycol dimethyl ether complex (NiCl₂ DME); a ligand such as1,10-phenanthroline; additives sodium tetrafluoroborate (NaBF₄),manganese powder (Mn), and 4-ethylpyridine; in a solvent such as MeOH;at a temperature of about 60° C. for a period of 16-20 h. tert-Butyl4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate isprepared from tert-butyl4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate usingdibromodifluoromethane (CBr₂F₂) with a suitable base such as sodiumhydride (NaH) and potassium tert-butoxide (KOtBu), and the like; in asuitable solvent such as N,N-dimethylacetamide (DMA), and the like.4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine is prepared fromtert-butyl4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate)using silver tetrafluoroborate (AgBF₄) in a solvent such as DCM, and thelike; in a temperature range of −78° C. to rt over a period of 16 h.

According to SCHEME 8, tert-butyl4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate is prepared viaSonogashira reaction of commercially available or syntheticallyaccessible tert-butyl 4-ethynylpiperidine-1-carboxylate and2-amino-3-bromopyridine; cuprous iodide; a catalyst such asbis(triphenylphosphine)palladium(II) dichloride, and the like; a basesuch as TEA, and the like; in a solvent such as N,N-dimethylformamide(DMF), and the like; at a temperature of about 100° C. for a period of15 h. tert-Butyl4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate is preparedfrom tert-butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylateusing an appropriate base such as KOtBu, and the like; in a suitablesolvent such as N-methyl-2-pyrrolidone (NMP), and the like; at atemperature of about 70° C. over a period of 16 h.

According to SCHEME 9, cleavage of the BOC protecting group ontert-butyl 4-bromopiperidine-1-carboxylate is achieved according tomethods previously described to give 4-bromopiperidine. A compound offormula (XIX), where R^(2a) and R^(2b) are H or CH₃, and X is CH₂ or O,is prepared by conventional amide bond forming techniques such ascoupling reactions which are well known to those skilled in the art(such as HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), BOP(benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), or conversion of the acid to an acid chloride).For example, reaction of a 4-bromopiperidine with a syntheticallyaccessible, suitably substituted compound of formula (XXII) (whichincludes compounds of formulas (XI) and (XV)), where R^(2a) and R^(2b)are H or CH₃, and X is CH₂ or O, where the acid is activated with anappropriate activating reagent, for example a carbodiimide, such asN,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) optionally in thepresence of hydroxybenzotriazole (HOBt) and/or a catalyst such as4-dimethylaminopyridine (DMAP); a halotrisaminophosphonium salt such asBOP, or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®); asuitable pyridinium salt such as 2-chloro-1-methyl pyridinium chloride;or another suitable coupling agent such asN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU), HATU,2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide(T3P®), and the like. Coupling reactions are conducted in a suitablesolvent such as DCM, THF, DMF, and the like; optionally in the presenceof a tertiary amine such as N-methylmorpholine, diisopropylethylamine(DIPEA), or TEA, at a temperature ranging from 0° C. to rt, to provide(2s,4s)-2-(4-bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.A compound of formula (XIX), where R^(2a), R^(2b) are H and X is O, issubjected to coupling conditions previously described with abromobenzene compound of formula R³—Br, where R³ is phenyl substitutedwith one, two or three members independently selected from: halo,OC₁₋₆haloalkyl, and C₁₋₆haloalkyl, to provide a compound of Formula (I)where R^(5a) and R^(5b) are H.

According to SCHEME 10, tert-butyl 4-bromopiperidine-1-carboxylate issubjected to coupling conditions as previously described; with acompound of formula R³—Br, where R³ is phenyl or pyridyl substitutedwith one, two, or three members selected from: halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆cycloalkyl, OC₁₋₆haloalkyl, phenyl, Ophenyl,Opyridyl, Si(CH₃)₃, SF₅, OC₁₋₄cycloalkyl, C(CH₃)₂OH, or OC₁₋₆alkyl; toprovide a compound of formula (XX). Cleavage of the BOC protecting groupon a compound of formula (XX) is achieved according to methodspreviously described to give a compound of formula (XXI). A compound offormula (XXI) is coupled with a commercially available or syntheticallyaccessible compound of formula (XXII) (which includes compounds offormulas (XI) and (XV)), where R^(2a) and R^(2b) are H or CH₃, and X isCH₂ or O, employing amide bond coupling methodologies as previouslydescribed, to provide a compound of Formula (I), where R⁴, R^(5a) andR^(5b) are H.

According to SCHEME 11, a compound of formula (XXIV), where R^(5a) andR^(5b) are each independently H or CH₃, is reacted in a metal-mediatedcross coupling reaction; with a suitably substituted aryl or heteroarylboronic acid, boronic ester, and the like; under Suzuki conditions knownto one skilled in the art; in the presence of a palladium catalyst suchas(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (RuPhos-Pd-G3),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), andthe like; a base such as K₃PO₄, K₂CO₃, Na₂CO₃, Cs₂CO₃, and the like;potassium fluoride; in a suitable solvent such as 1,4-dioxane, DMF,ethanol, water, or a mixture thereof, at temperatures ranging from 60 to150° C.; employing conventional or microwave heating; to provide acompound of formula (XXV). A compound of formula (XXV) is treated withbenzyl bromide in a solvent such as ACN, and the like; to provide acompound of formula (XXVI). A compound of formula (XXVI) is treated witha reducing agent such as NaBH₄, and the like; in a solvent such as MeOH,and the like; to provide a compound of formula (XXVII). A compound offormula (XXVII) is reacted under hydrogenation conditions known to oneskilled in the art, for example employing H₂ in the presence of acatalyst such as Pd/C, and the like, in a suitable solvent such as MeOH,and the like, to provide a compound of formula (XXVIII). A compound offormula (XXVIII) is reacted under amide coupling conditions aspreviously described with a compound of formula (XXII) (which includescompounds of formulas (XI) and (XV)), where R^(2a) and R^(2b) are H orCH₃, and X is CH₂ or O, to provide a compound of Formula (I), where R⁴is H.

According to SCHEME 12, 4-bromo-3-methylpyridine is alkylated employingconditions with benzyl bromide previously described to provide1-benzyl-4-bromo-3-methylpyridin-1-ium bromide.1-Benzyl-4-bromo-3-methylpyridin-1-ium bromide is reduced employingconditions previously described to provide1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine.1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridineis is reacted with asuitably substituted aryl or heteroaryl boronic acid of formula (XXIII);employing Suzuki coupling conditions previously described, to provide acompound of formula (XXVII). A compound of formula (XXVII) is submittedto hydrogenation conditions as previously described to provide acompound of formula (XXVIII). A compound of formula (XXVIII) is reactedunder amide coupling conditions as previously described with a compoundof formula (XXII) (which includes compounds of formulas (XI) and (XV)),where R^(2a) and R^(2b) are H or CH₃, and X is CH₂ or O, to provide acompound of Formula (I), where R⁴ is H, R^(5a) is H, and R^(5b) is CH₃.

According to SCHEME 13, an appropriately substituted aryl bromide suchas 2-bromo-6-tert-butylpyridine is treated with n-BuLi; in a suitablesolvent such as THF, and the like; 1-boc-4-piperidone; at temperaturesranging from −78° C. to room temperature; for period of 1-3 hrs; toprovide tert-butyl4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate,tert-Butyl4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate isreacted with a halogenating reagent such as thionyl chloride (SOCl₂),and the like; a catalyst such as 4-(dimethylamino)pyridine (DMAP), andthe like; in a suitable solvent such as pyridine, and the like; toprovide tert-butyl6-(tert-butyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate.tert-Butyl6-(tert-butyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate isreacted under hydrogenation conditions as previously described, toprovide a compound of formula (XX), where R³ is pyridine substitutedwith C₁₋₆alkyl. Cleavage of the BOC protecting group on a compound offormula (XX) is achieved according to methods known to one skilled inthe art or as previously described, to give a compound of formula (XXI).A compound of formula (XXI) is reacted under amide coupling conditionsas previously described, with a compound of formula (XXII) (whichincludes compounds of formulas (XI) and (XV)), where R^(2a) and R^(2b)are H or CH₃, and X is CH₂ or O, to provide a compound of Formula (I),where R⁴ is H.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to one of ordinary skill in the art. For example, anamine of Formula (I) is treated with trifluoroacetic acid, HCl, orcitric acid in a solvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, orisopropanol to provide the corresponding salt form. Alternately,trifluoroacetic acid or formic acid salts are obtained as a result ofreverse phase HPLC purification conditions. Crystalline forms ofpharmaceutically acceptable salts of compounds of Formula (I) may beobtained in crystalline form by recrystallization from polar solvents(including mixtures of polar solvents and aqueous mixtures of polarsolvents) or from non-polar solvents (including mixtures of non-polarsolvents).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Compounds prepared according to the schemes described above may beobtained as single forms, such as single enantiomers, by form-specificsynthesis, or by resolution. Compounds prepared according to the schemesabove may alternately be obtained as mixtures of various forms, such asracemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic andnon-racemic mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one ofordinary skill in the art, such as chiral chromatography,recrystallization, diastereomeric salt formation, derivatization intodiastereomeric adducts, biotransformation, or enzymatic transformation.Where regioisomeric or diastereomeric mixtures are obtained, asapplicable, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

EXAMPLES

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Reactions under microwave irradiation conditions were carriedout in a Biotage Initiator or CEM (Microwave Reactor) Discoverinstrument.

For the reactions conducted under continuous flow conditions, “flowedthrough a LTF-VS mixer” refers to the use of a Chemyx Fusion 100 TouchSyringe Pump that is in line via 1/16″ PTFE tubing to a LTF-VS mixer(Little Things Factory GmbH (http://www.ltf-gmbh.com), unless otherwiseindicated.

Normal-phase silica gel chromatography (FCC) was performed on silica gel(SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RPHPLC) was performed on either:

METHOD A. An Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30×100or 50×150 mm) or an XBridge C18 OBD column (5 μM, 30×100 or 50×150 mm),and a mobile phase of 5% ACN in 20 mM NH40H was held for 2 min, then agradient of 5-99% ACN over 15 min, then held at 99% ACN for 5 min, witha flow rate of 40 or 80 mL/min.

or

METHOD B. A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3μm, 30×100 mm, T=45° C.), mobile phase of 5% ACN in H₂O (both with 0.05%TFA) was held for 1 min, then a gradient of 5-99% ACN over 6 min, thenheld at 99% ACN for 3 min, with a flow rate of 80 mL/min.

or

METHOD C. A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5μm, 50×100 mm), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) washeld for 1 min, then a gradient of 5-99% ACN over 14 min, then held at99% ACN for 10 min, with a flow rate of 80 mL/min.

or

METHOD D. A Gilson HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5-99% ACN in 20 mM NH₄OH over 10 min and then hold at 99ACN for 2 min, at a flow rate of 80 mL/min.

or

METHOD E. An ACCQ Prep HPLC with an XBridge C18 OBD column (5 μM,50×100), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) was heldfor 1 min, then a gradient of 5-95% ACN over 12 min, then held at 95%ACN for 2 min, with a flow rate of 80 mL/min.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed either on a Jasco preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted at 100 to 150bar with a flow rate ranging from 40 to 60 mL/min. The column was heatedto 35 to 40° C.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. Definitions for multiplicity are as follows:s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, hept=heptet,dd=doublet of a doublet, dt=doublet of a triplet, pd=pentet of adoublet, ddd=doublet of a doublet of a doublet, tp=triplet of a pentet,td=triplet of a doublet, qd=quartet of a doublet, dq=doublet of aquartet, tt=triplet of a triplet, td=triplet of a doublet, m=multiplet,br=broad. It will be understood that for compounds comprising anexchangeable proton, said proton may or may not be visible on an NMRspectrum depending on the choice of solvent used for running the NMRspectrum and the concentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoftCorp., Cambridge, Mass.) or OEMetaChem V1.4.0.4 (Open Eye).

Compounds designated as R* or S* are enantiopure compounds where theabsolute configuration was not determined.

Intermediate 1: tert-Butyl 3-nitrocyclobutanecarboxylate

Step A: tert-Butyl 3-hydroxyiminocyclobutanecarboxylate. To a solutionof tert-butyl 3-oxocyclobutane-1-carboxylate (100 g, 588 mmol) in EtOH(1.8 L) was added NaOAc (192 g, 2340 mmol) and hydroxylaminehydrochloride (81 g, 1166 mmol). The reaction mixture was stirred atreflux for 4 h then filtered through a pad of Celite® and the pad waswashed with EtOH. The combined filtrates were evaporated under reducedpressure and the residue was taken up in EtOAc and washed with water andbrine. The organic layer was dried over magnesium sulfate, filtered andevaporated under reduced pressure to give the title compound (108 g, 99%yield) as a white solid. MS (ESI): mass calcd. for C₉H₁₅NO₃ 185.1; m/zfound, 186.2 [M+H]⁺.

Step B: tert-Butyl 3-nitrocyclobutanecarboxylate. To a suspension ofurea hydrogen peroxide (164 g, 1.74 mol) in ACN (1 L) was added asolution of TFAA (245 mL, 1.75 mol) in ACN (500 mL) dropwise over 1 h at−10° C. The reaction mixture was stirred at room temperature for 1 h.This was added to a solution of tert-butyl3-hydroxyiminocyclobutanecarboxylate (108 g, 0.584 mol) and sodiumphosphate dibasic (911 g, 6.42 mol) in ACN (1 L) dropwise over 30 min at80° C. The reaction mixture was stirred at 80° C. for 30 min thenfiltered through a pad of Celite® and the pad was washed with ACN. Thecombined filtrates were diluted with EtOAc and the mixture was washedwith water and brine. The organic layer was dried over magnesiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by flash column chromatography (FCC) on silica (0-20% EtOAc inheptane) to give the title compound (89.6 g, 76% yield) as a yellow oilas a 1.3:1 mixture of cis/trans isomers. Compound does not ionize withESI⁺ LCMS.

Intermediate 2: Ethyl 3-nitrocyclobutanecarboxylate

The title compound was prepared in a manner analogous to Intermediate 1using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl3-oxocyclobutane-1-carboxylate in Step A. Compound does not ionize withESI⁺ LCMS. ¹H NMR (300 MHz, CDCl₃) δ 5.02-4.70 (m, 1H), 4.20 (q, J=7.2Hz, 2H), 3.04-2.71 (m, 5H), 1.29 (t, J=7.0 Hz, 3H).

Intermediate 3: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicAcid

Step A: tert-Butyl(1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate. To asolution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1,89.6 g, 445 mmol) in MeCN (1 L) was added formaldehyde (37 wt % inwater, 73 mL, 971 mmol). To the reaction mixture was added triethylamine(TEA) (62 mL, 444 mmol) dropwise at 0° C. and the reaction was stirredat room temperature for 2 h. The reaction mixture was evaporated and theresidue was purified by FCC on silica (0-25% EtOAc in heptane) to givethe title compound (38.2 g, 165 mmol, 37% yield) as a white powder. MS(ESI): mass calcd. for C₁₀H₁₇NO₅ 231.2; m/z found, 254.1 [M+Na]⁺.trans-tert-Butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate wasformed, but not isolated.

Step B: tert-Butyl(1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate. To asolution of tert-butyl(1s,3s)-3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate (38 g, 165mmol) in EtOAc (600 mL) was added 10% palladium on carbon (Pd/C) (1.9g). The reaction mixture was stirred at 50° C. for 1 h under hydrogen(H2) (10 bar). The reaction mixture was filtered through a pad ofCelite®. To the filtrate was added 10% Pd/C (1.9 g). The reactionmixture was stirred at 50° C. for 2 h under H2 (10 bar). The reactionmixture was filtered through a pad of Celite® and the Celite® was washedwith EtOAc. The combined filtrates were evaporated and the residue wastriturated with diethyl ether (Et₂O) to give the title compound (18.6 g,92.4 mmol, 55% yield) as a white powder. MS (ESI): mass calcd. forC₁₀H₁₉NO₃ 201.1; m/z found, 202.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6) δ5.26-3.98 (m, 1H), 3.74-2.94 (m, 4H), 2.70-2.57 (m, 1H), 2.20-2.07 (m,2H), 1.97-1.82 (m, 2H), 1.39 (s, 9H).

Step C: tert-Butyl(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solutionof tert-butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate(18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL) was added TEA (26mL, 186 mmol). To the mixture was added a solution of triphosgene (9.6g, 32.4 mmol) in THF (200 mL) dropwise at −10° C. and stirred at roomtemperature for 1 h. The reaction mixture poured into saturated sodiumbicarbonate (600 mL) and the mixture was extracted with EtOAc. Thecombined organic layers were dried over magnesium sulfate, filtered, andevaporated. The residue was triturated with Et₂O to give the titlecompound (17.7 g, 77.9 mmol, 84% yield) as a white powder. MS (ESI):mass calcd. for C₁₁H₁₇NO₄ 227.1; m/z found, 228.2 [M+H]⁺.

Step D: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. Totrifluoroacetic acid (TFA) (180 mL, 235 mmol) was added tert-butyl(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (17.7 g, 77.9mmol) in portions at 0° C. The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was evaporated and the residuewas triturated with Et₂O to afford the title compound (12.9 g, 75.4mmol, 96% yield) as a white powder. MS (ESI): mass calcd. for C₇H₉NO₃171.0; m/z found, 172.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (br s,1H), 8.08 (s, 1H), 4.34 (s, 2H), 2.79-2.66 (m, 1H), 2.43-2.29 (m, 4H).

Intermediate 4: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic Acid

Step A: Ethyl(1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate. To asolution of ethyl 3-nitrocyclobutanecarboxylate (Intermediate 2, 16.6 g,95.6 mmol) in MeCN (145 mL) was added methyl acrylate (10.3 mL, 114mmol). To the reaction mixture was added1,8-diazabicyclo[5.4.0]undec-7-ene (7.1 mL, 47.6 mmol) dropwise at 0° C.and the reaction mixture was stirred at 0° C. for 1 h. The reactionmixture was diluted with saturated ammonium chloride and EtOAc and thelayers were separated. The organic layer was dried over magnesiumsulfate, filtered and evaporated. The residue was purified by FCC onsilica (0-15% EtOAc in heptane) to give the title compound (13.6 g, 52.6mmol, 55% yield) as a colorless liquid. MS (ESI): mass calcd. forC₁₁H₁₇NO₆ 259.1; m/z found, 282.1 [M+Na]⁺. ¹H NMR (300 MHz,Chloroform-d) δ 4.17 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.12-2.79 (m, 3H),2.69-2.49 (m, 2H), 2.48-2.21 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).

Step B: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid. To asolution of ethyl(1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate (13.6g, 52.5 mmol) in methanol (MeOH) (133 mL) was added nickel(II) chloridehexahydrate (12.5 g, 52.6 mmol). To the reaction mixture was addedsodium borohydride (NaBH₄) (10 g, 264 mmol) in small portions at −10° C.and the reaction mixture was stirred at 0° C. for 1 h. To the reactionmixture was added aqueous potassium carbonate (47 mL, 141 mmol, 3 M)dropwise at 0° C. (pH 10) and the reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was filtered through a pad of Celite® andthe pad was washed with EtOH. The combined filtrates were evaporated.The residue was purified by FCC on silica eluting withchloroform:methanol:acetic acid (100:0:0→9:1:1) to give the titlecompound (4.8 g, 28.2 mmol, 53% yield) as an off-white powder. MS (ESI):mass calcd. for C₈H₁₁NO₃ 169.1; m/z found, 170.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 7.97 (br s, 1H), 4.01-2.94 (m, 1H), 2.82-2.65 (m, 1H),2.36-2.01 (m, 8H).

Intermediate 5: cis-tert-Butyl3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate

Step A: tert-Butyl 3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate. Toa solution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1,11.7 g, 58.1 mmol) in ACN (120 mL) was added acetaldehyde (19.6 mL, 349mmol). To the reaction mixture was added TEA (8.1 mL, 58 mmol) dropwiseat 0° C. and the reaction mixture was stirred at room temperature for 18h. The reaction mixture was evaporated under reduced pressure and theresidue was purified by FCC on silica (0-20% EtOAc in heptane) to givethe title compound (10.5 g) as a colorless oil in a mixture of cis andtrans isomers. MS (ESI): mass calcd. for C₁₁H₁₉NO₅ 245.1; m/z found,263.2 [M+H+NH₃]⁺.

Step B: tert-Butyl(1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate. To asolution of a tert-butyl3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate (10.5 g, 42.8 mmol) inEtOAc (110 mL) was added 10% Pd/C (1 g). The reaction mixture wasstirred at 50° C. for 1 h under H2 (10 bar). The reaction mixture wasfiltered through a pad of Celite®. To the filtrate was added 10% Pd/C(500 mg) and the reaction mixture was stirred at 50° C. for 2 h under H2(10 bar). The reaction mixture was filtered through a pad of Celite® andthe pad was washed with EtOAc. The combined filtrates were evaporatedand the residue was purified by FCC on silica eluting withchloroform:methanol:ammonium hydroxide (1:0:0→9:1:0.05) to give thetitle compound (3.6 g, 16.7 mmol, 39% yield) as a yellow oil. MS (ESI):mass calcd. for C₁₁H₂₁NO₃ 215.2; m/z found, 216.3 [M+H]⁺. ¹H NMR (300MHz, Chloroform-d) δ 3.83-3.64 (m, 1H), 2.80-2.61 (m, 1H), 2.54 (br s,2H), 2.52-2.27 (m, 3H), 2.14-1.93 (m, 2H), 1.45 (s, 9H), 1.22-1.13 (m,3H). Additional fractions from the same purification were collected togive tert-butyl (1r,3r)-3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate(550 mg) as a yellow oil.

Intermediate 6:(2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic Acid

Step A: cis-tert-Butyl8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solutionof tert-butyl(1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate(Intermediate 5, 15.2 g, 70.4 mmol) in THF (240 mL) was added TEA (20mL, 143 mmol). To the mixture was added a solution of triphosgene (7.3g, 24.6 mmol) in THF (170 mL) dropwise at −10° C. and the reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas poured into saturated NaHCO₃ and extracted with EtOAc. The combinedorganic layers were dried over magnesium sulfate, filtered, andevaporated under reduced pressure. The residue was purified by FCC onsilica (0-35% EtOAc in heptane) to give the title compound (9.0 g, 52%yield) as a white powder. MS (ESI): mass calcd. for C₁₂H₁₉NO₄ 241.1; m/zfound, 242.2 [M+H]⁺.

Step B: (2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid. To TFA (60 mL, 784 mmol) was added cis-tert-butyl8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (6.1 g, 25.3mmol) in portions at 0° C. and the reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was evaporated under reducedpressure and the residue was triturated with Et₂O to give the titlecompound (4.3 g, 91% yield) as a white powder. MS (ESI): mass calcd. forC₈H₁₁NO₄ 185.1; m/z found, 186.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ12.23 (br s, 1H), 7.94 (s, 1H), 4.50 (q, J=6.4 Hz, 1H), 2.68-2.59 (m,1H), 2.53-2.46 (m, 1H), 2.41-2.35 (m, 1H), 2.32-2.24 (m, 1H), 2.17 (dd,J=12.0, 10.1 Hz, 1H), 1.30 (d, J=6.5 Hz, 3H).

Intermediate 7:(2s,4s)-8,8-Dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic Acid

Step A: cis-tert-Butyl3-(tert-butoxycarbonylamino)-3-(1-hydroxyethyl)cyclobutanecarboxylate.To a solution of cis-tert-butyl3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate (Intermediate 5, 3.1 g,14.4 mmol) in DCM (60 mL) was added di-tert-butyl dicarbonate (3.5 g, 16mmol) and TEA (4 mL, 28.7 mmol). The reaction mixture was stirred atroom temperature for 3 h. To the reaction mixture was added water andDCM. The layers were separated, and the organic layer was dried oversodium sulfate, filtered, and evaporated under reduced pressure. Theresulting residue was purified by FCC on silica (25% EtOAc in heptane)to give the title compound (3.0 g, 66% yield) as a white powder. MS(ESI): mass calcd. for C₁₆H₂₉NO₅ 315.2; m/z found, 338.2 [M+Na]⁺. ¹H NMR(500 MHz, CDCl₃) δ 4.89 (s, 1H), 3.88 (q, J=6.3 Hz, 1H), 3.36-2.93 (m,1H), 2.91-2.74 (m, 2H), 2.30-2.18 (m, 2H), 2.18-2.09 (m, 1H), 1.44 (s,9H), 1.42 (s, 9H), 1.13 (d, J=6.3 Hz, 3H).

Step B: cis-tert-Butyl3-acetyl-3-(tert-butoxycarbonylamino)cyclobutanecarboxylate. To asolution of cis-tert-butyl3-(tert-butoxycarbonylamino)-3-(1-hydroxyethyl)cyclobutanecarboxylate(3.0 g, 9.51 mmol) in DCM (60 mL) was added DMP (4.8 g, 11.4 mmol) at10° C. and the reaction mixture was stirred at room temperature for 3 h.To the reaction mixture was added saturated NaHCO₃ and DCM. The layerswere separated, and the organic layer was dried over sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby FCC on silica (0-25% EtOAc in heptane) to give the title compound(2.6 g, 8.17 mmol, 85% yield) as a white powder. MS (ESI): mass calcd.for C₁₆H₂₇NO₅ 313.19; m/z found, 336.2 [M+Na]⁺. ¹H NMR (500 MHz, CDCl₃)δ 5.29 (s, 1H), 2.93-2.81 (m, 1H), 2.80-2.69 (m, 2H), 2.16 (s, 3H),2.25-2.09 (m, 2H), 1.43 (s, 9H), 1.42-1.36 (m, 9H).

Step C: cis-tert-Butyl3-(tert-butoxycarbonylamino)-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate.To a solution of cis-tert-butyl3-acetyl-3-(tert-butoxycarbonylamino)cyclobutanecarboxylate (2.5 g, 7.98mmol) in THF (50 mL) was added methylmagnesium bromide (8 mL, 24 mmol, 3M in Et₂O) dropwise at −40° C. The reaction mixture was stirred at −40°C. for 1 h. The reaction mixture was diluted with ammonium chloride andextracted with EtOAc. The combined organic layers were dried over sodiumsulfate, filtered and evaporated under reduced pressure. The residue waspurified by FCC on silica (0-20% EtOAc in heptane) to give the titlecompound (650 mg, 24% yield) as a white powder. MS (ESI): mass calcd.for C₁₇H₃₁NO₅ 329.2; m/z found, 174.2 [M+H−tBu−Boc]⁺. ¹H NMR (500 MHz,CDCl₃) δ 4.91 (br s, 1H), 4.11-2.93 (m, 1H), 2.88-2.78 (m, 1H),2.64-2.55 (m, 2H), 2.30-2.18 (m, 2H), 1.44 (s, 9H), 1.42 (s, 9H), 1.21(s, 6H).

Step D: cis-tert-Butyl3-amino-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate. To asolution of cis-tert-butyl3-(tert-butoxycarbonylamino)-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate(650 mg, 1.97 mmol) in DCM (13 mL) was added TFA (1.2 mL, 15.7 mmol) andthe reaction mixture was stirred at room temperature for 1 h. To thereaction mixture was added saturated sodium carbonate and DCM. Thelayers were separated, and the organic layer was dried over sodiumsulfate, filtered and evaporated under reduced pressure to give thetitle compound (430 mg, 95% yield) as a yellow oil. MS (ESI): masscalcd. for C₁₂H₂₃NO₃ 229.2; m/z found, 230.4 [M+H]⁺.

Step E: cis-tert-Butyl8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To asolution of cis-tert-butyl3-amino-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate (630 mg, 2.75mmol) in THF (10 mL) was added TEA (770 μL, 5.52 mmol). To the mixturewas added a solution of triphosgene (285 mg, 0.96 mmol) in THF (7.5 mL)dropwise at −10° C. and the reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into saturatedNaHCO₃ and extracted with EtOAc. The combined organic layers were driedover magnesium sulfate, filtered and evaporated under reduced pressure.The residue was purified by FCC on silica (0-35% EtOAc in heptane) togive the title compound (520 mg, 74% yield) as a white powder. MS (ESI):mass calcd. for C₁₃H₂₁NO₄ 255.2; m/z found, 256.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 6.06 (br s, 1H), 2.73-2.63 (m, 3H), 2.28-2.17 (m, 2H),1.45 (s, 9H), 1.39 (s, 6H).

Step F:(2s,4s)-8,8-Dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid. To TFA (5.2 mL, 67.9 mmol) was added cis-tert-butyl8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (520 mg,2.04 mmol) in portions at 0° C. and the reaction mixture was stirred atroom temperature for 1 h. The reaction mixture was evaporated underreduced pressure and the residue was triturated with Et₂O to give thetitle compound (330 mg, 81% yield) as a white powder. MS (ESI): masscalcd. for C₉H₁₃NO₄ 199.1; m/z found, 200.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 12.25 (s, 1H), 7.84 (s, 1H), 2.76-2.41 (m, 3H), 2.33-2.17 (m,2H), 1.38 (s, 6H).

Intermediate 8: 4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine

Step A: tert-Butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate.In an oven-dried pressure vial, N-boc-4-bromopiperidine (200 mg, 0.742mmol) was combined with 5-bromo-2-methylphenol (146 mg, 0.742 mmol),NiCl₂ (DME) (33 mg, 0.148 mmol), 1,10-phenanthroline (55 mg, 0.297mmol), NaBF₄ (42 mg, 0.371 mmol), and Mn (81 mg, 1.48 mmol). This wastaken up in anhydrous MeOH (3.7 mL) and 4-ethylpyridine (43 μL, 0.371mmol) was added. The vial was capped, purged with nitrogen (N2), andheated at 60° C. for 18 hours. The mixture was diluted with EtOAc,filtered through Celite®, and concentrated under reduced pressure.Purification via FCC on silica (0-30% EtOAc in hexane) afforded thetitle compound (116 mg, 54% yield). MS (ESI): mass calcd. for C₁₇H₂₅NO₃291.2; m/z found, 236.1 [M+2H−tBu]⁺.

Step B: tert-Butyl4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate. Inan oven-dried flask under N2, tert-butyl4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate (108 mg, 0.371mmol) was taken up in DMA (0.75 mL) and cooled to 0° C. To this wasadded NaH (71 mg, 1.85 mmol) and the mixture was warmed to roomtemperature and stirred for 1.5 h. After cooling to 0° C., a solution ofCBr₂F₂ (0.29 mL, 2.96 mmol) in DMA (0.75 mL) was added dropwise and thiswas stirred for 3 h at room temperature. Cooled back to 0° C. to addKOtBu (127 mg, 1.11 mmol) before heating to 80° C. for 24 h. Cooled thereaction, added water, extracted with EtOAc, dried over sodium sulfate(Na₂SO₄) and concentrated under reduced pressure. The resulting residuewas purified by FCC on silica (0-50% EtOAc in hexane) to provide thetitle compound (36 mg, 23% yield).

Step C: 4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine. To a solutionof tert-butyl4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate (50mg, 0.119 mmol) in DCM (1.2 mL) at −78° C. was added AgBF₄ (52 mg, 0.262mmol). The reaction was allowed to warm to room temperature and stirredfor 16 h. The resulting mixture was filtered through a PTFE filter withMeOH and concentrated under reduced pressure to provide the titlecompound which was used without further purification in the next step.MS (ESI): mass calcd. for C₁₃H₁₆F₃NO 259.1; m/z found, 260.1 [M+H]⁺.

Intermediate 9: tert-Butyl4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate

Step A: tert-Butyl4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate. A solution of2-amino-3-bromopyridine (200 mg, 1.156 mmol),bis(triphenylphosphine)palladium(II) dichloride (42 mg, 0.060 mmol),tert-butyl 4-ethynylpiperidine-1-carboxylate (240 mg, 1.147 mmol),cuprous iodide (22 mg, 0.116 mmol), and TEA (1 mL, 7.194 mmol) in DMF (2mL, previously sparged with N2) was heated in a sealed pressure vial at100° C. under N2. After 15 h, the reaction was cooled to roomtemperature and the mixture was filtered through Celite® using EtOAc aseluent. The filtrate was washed with brine, dried (Na₂SO₄), filtered,and concentrated under reduced pressure. Purification via FCC on silica(0-100% EtOAc in hexane) provided the title compound as a brown oil (209mg, 60% yield). MS (ESI): mass calcd. for C₁₇H₂₃N₃O₂ 301.2; m/z found,302.2 [M+H]⁺.

Step B: tert-Butyl4-(1H-pyrrolo[2,3-b]pyridin-2-yl)pipridine-1-carboxylate. To a solutionof tert-butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate(183 mg, 0.607 mmol) in NMP (1.8 mL) was added KOtBu (1.8 mL, 1 M inTHF) dropwise via syringe at room temperature under N2. The resultingsolution was heated to 70° C. for 16 h. This was then diluted with waterand extracted with EtOAc. The organic layers were combined, washed withbrine, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. Purification via FCC on silica (0-100% EtOAc in hexane)provided the title compound as an off-white solid (93 mg, 51% yield). MS(ESI): mass calcd. for C₁₇H₂₃N₃O₂ 301.2; m/z found, 302.2 [M+H]⁺.

Intermediate 10:(racemic-(cis)-3-Methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 4-methyl-3-(trifluoromethyl)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid.

Intermediate 11:(2s,4s)-2-(4-Bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

To N-boc-4-bromopiperidine (210 mg, 0.795 mmol) in MeOH (1 mL) was addedhydrochloric acid (HCl) in 1,4-dioxane (4 M, 1.5 mL). This was heated to45° C. for 1 hour before concentrating under reduced pressure. Theresidue was re-dissolved in DMF (2 mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 179 mg, 1.05 mmol), DIPEA (0.32 mL, 1.85 mmol), and(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU) (410 mg, 1.05 mmol). This was stirredat room temperature for 2 hours. The reaction mixture was filteredthrough a PTFE filter with MeOH and purified via reverse phase HPLC(5-95% ACN in 20 mM NH40H in water) to afford the title compound (117mg, 46% yield). MS (ESI): mass calcd. for C₁₂H₁₇BrN₂O₃ 316.0; m/z found,317.0 [M+H]⁺.

Intermediate 12: 1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine

Step A: 1-Benzyl-4-bromo-3-methylpyridin-1-ium bromide.4-bromo-3-methylpyridine (500 mg, 2.9 mmol) and benzyl bromide (0.41 mL,3.5 mmol) were dissolved in ACN (5 mL) and stirred overnight at 70° C.The reaction mixture was washed with hexanes, concentrated under reducedpressure, and used directly in the next step without purification. MS(ESI): mass calcd. for C₁₃H₁₃BrN, 262.0; m/z found, 262.0 [M]⁺.

Step B: 1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine.1-Benzyl-4-bromo-3-methylpyridin-1-ium bromide from Step A was dissolvedin MeOH (10 mL) and the reaction mixture was cooled to 0° C. NaBH₄ (330mg, 8.7 mmol) was added slowly with stirring. The reaction mixture wasstirred at 0° C. for 30 minutes, concentrated under reduced pressure,and partitioned between DCM and water. The organic layer wasconcentrated under reduced pressure and purified by FCC on silica (0-50%EtOAc in hexanes) to obtain the title compound (381 mg, 49% yield). MS(ESI): mass calcd. for C₁₃H₁₆BrN, 265.0; m/z found, 266.0 [M+H]⁺.

Intermediate 13: 4-(3-(tert-Butyl)phenyl)-3-methylpyridine

4-bromo-3-methylpyridine (1.0 g, 5.8 mmol), 4-(tert-butyl)phenylboronicacid (1.2 g, 7.0 mmol), cesium carbonate (5.7 g, 17 mmol) and2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (RuPhos Pd G3) (243 mg, 0.29 mmol) were taken up in1,4-dioxane (40 mL) and the reaction mixture was stirred at 100° C.overnight under N2. The reaction mixture was concentrated under reducedpressure to remove solvent and the residue was partitioned between DCMand water. The aqueous layer was extracted with DCM and the combinedorganics were concentrated under reduced pressure and purified by FCC onsilica (0-100% EtOAc in hexanes) to obtain the title compound (805 mg,61% yield). MS (ESI): mass calcd. for C₁₆H₁₉N, 225.2; m/z found, 226.2[M+H]⁺.

Intermediate 14: 4-(4-(tert-Butyl)phenyl)-2-methylpyridine

The title compound was prepared in a manner analogous to4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13) using4-(tert-butyl)phenylboronic acid instead of 3-(tert-butyl)phenylboronicacid and 4-bromo-2-methylpyridine instead of 4-bromo-3-methylpyridine.MS (ESI): mass calcd. for C₁₆H₁₉N, 225.2; m/z found, 226.2 [M+H]⁺.

Intermediate 15: 4-(4-(Trifluoromethyl)phenyl)-2-methylpyridine

The title compound was prepared in a manner analogous to4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13) using4-(trifluoromethyl)phenylboronic acid instead of3-(tert-butyl)phenylboronic acid and 4-bromo-2-methylpyridine instead of4-bromo-3-methylpyridine. MS (ESI): mass calcd. for C₁₃H₁₀F₃N, 237.1;m/z found, 238.1 [M+H]⁺.

Intermediate 16: 4-(3-(tert-Butyl)phenyl)-2-methylpyridine

The title compound was prepared in a manner analogous to4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13) using4-bromo-2-methylpyridine instead of 4-bromo-3-methylpyridine. MS (ESI):mass calcd. for C₁₋₆H19N, 225.2; m/z found, 226.2 [M+H]⁺.

Intermediate 17: 4-([1,1′-Biphenyl]-3-yl)-3-methylpyridine

The title compound was prepared in a manner analogous to4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13) usingbiphenyl-3-boronic acid instead of 3-(tert-butyl)phenylboronic acid. MS(ESI): mass calcd. for C₁₈H₁₅N, 245.1; m/z found, 246.0 [M+H]⁺.

Intermediate 18:1-Benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine

The title compound was prepared in a manner analogous to1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12)using 4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13)instead of 4-bromo-3-methylpyridine. MS (ESI): mass calcd. for C₂₃H₂₉N,319.2; m/z found, 320.3 [M+H]⁺.

Intermediate 19:1-Benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine

The title compound was prepared in a manner analogous to1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12)using 4-(4-(tert-butyl)phenyl)-2-methylpyridine (Intermediate 14)instead of 4-bromo-3-methylpyridine. MS (ESI): mass calcd. for C₂₃H₂₉N,319.2; m/z found, 320.3 [M+H]⁺. Alkene isomer was not definitivelydetermined.

Intermediate 20:1-Benzyl-6-methyl-4-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine

The title compound was prepared in a manner analogous to1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12)using 4-(4-(trifluoromethyl)phenyl)-2-methylpyridine (Intermediate 15)instead of 4-bromo-3-methylpyridine. MS (ESI): mass calcd. forC₂₀H₂₀F₃N, 331.2; m/z found, 332.1 [M+H]⁺. Alkene isomer was notdefinitively determined.

Intermediate 21:1-Benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine

The title compound was prepared in a manner analogous to1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12)using 4-(3-(tert-butyl)phenyl)-2-methylpyridine (Intermediate 16)instead of 4-bromo-3-methylpyridine. MS (ESI): mass calcd. for C₂₃H₂₉N,319.2; m/z found, 320.1 [M+H]⁺. Alkene isomer was not definitivelydetermined.

Intermediate 22:4-([1,1′-Biphenyl]-3-yl)-1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine

The title compound was prepared in a manner analogous to1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12)using 4-([1,1′-biphenyl]-3-yl)-3-methylpyridine (Intermediate 17)instead of 4-bromo-3-methylpyridine. MS (ESI): mass calcd. for C₂₅H₂₅N,339.2; m/z found, 340.3 [M+H]⁺.

Intermediate 23:(racemic)-(cis)-3-Methyl-4-(4-(tert-butylphenyl)piperidine

1-Benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine(Intermediate 18, 270 mg, 0.845 mmol) and 10% Pd/C (500 mg) were takenup in EtOAc (20 mL). The reaction vessel was evacuated and backfilledwith H₂. The reaction mixture was stirred at r.t. for 3 hours, filteredthrough Celite®, concentrated under reduced pressure, and used directlyin subsequent transformations without further purification (183 mg,0.791 mmol, 94% yield). MS (ESI): mass calcd. for C₁₆H₂₅N, 231.2; m/zfound, 232.2 [M+H]⁺.

Intermediate 24:(racemic)-(cis)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine

The title compound was prepared in a manner analogous to racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using4-([1,1′-biphenyl]-3-yl)-1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine(Intermediate 19) instead of1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine(Intermediate 18). MS (ESI): mass calcd. for C₁₈H₂₁N, 251.2; m/z found,252.1 [M+H]⁺.

Intermediate 25: 4-(4-(tert-Butyl)phenyl)-2-methylpiperidine

The title compound (mixture of four diasteriomers) was prepared in amanner analogous to racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using1-benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine(Intermediate 19) instead of1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine(Intermediate 18). MS (ESI): mass calcd. for C₁₈H₂₁N, 251.2; m/z found,252.1 [M+H]⁺.

Intermediate 26: 4-(4-(Trifluoromethyl)phenyl-2-methylpiperidine

The title compound (mixture of four diasteriomers) was prepared in amanner analogous to racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using1-benzyl-6-methyl-4-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine(Intermediate 20) instead of1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine(Intermediate 18). MS (ESI): mass calcd. for C₁₃H₁₆F₃N, 243.1; m/zfound, 244.1 [M+H]⁺.

Intermediate 27: 4-(3-(tert-Butyl)phenyl)-2-methylpiperidine

The title compound (mixture of four diasteriomers) was prepared in amanner analogous to racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using1-benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine(Intermediate 21) instead of1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine(Intermediate 18). MS (ESI): mass calcd. for C₁₈H₂₁N, 251.2; m/z found,252.1 [M+H]⁺.

Intermediate 28:(racemic-(cis)-3-Methyl-4-(3-(trifluoromethoxy)phenyl)piperidine

Step A:1-Benzyl-5-methyl-4-(3-(trifluoromethoxy)phenyl)-1,2,3,6-tetrahydropyridine.1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12,100 mg, 0.38 mmol), 3-(trifluoromethoxy)phenylboronic acid (95 mg, 0.45mmol), cesium carbonate (367 mg, 1.13 mmol) and RuPhos Pd G3 (16 mg,0.019 mmol) were taken up in dioxane and the reaction mixture wasstirred at 100° C. overnight under N2. The reaction mixture wasconcentrated under reduced pressure to remove solvent and the residuewas partitioned between DCM and water. The aqueous layer was extractedwith DCM and the combined organics were concentrated under reducedpressure and purified by FCC on silica (0-100% EtOAc in hexanes) toobtain the title compound (70 mg, 0.20 mmol, 54% yield). MS (ESI): masscalcd. for C₂₀H₂₀F₃NO 347.2; m/z found, 348.1 [M+H]⁺.

Step B:(racemic)-(cis)-3-Methyl-4-(3-(trifluoromethoxy)phenyl)piperidine.1-Benzyl-5-methyl-4-(3-(trifluoromethoxy)phenyl)-1,2,3,6-tetrahydropyridine(70 mg, 0.20 mmol) and 10% Pd/C (50 mg) were taken up in EtOAc. Thereaction vessel was evacuated and backfilled with H₂, and the reactionmixture was stirred overnight at r.t., The mixture was filtered throughCelite®, and concentrated under reduced pressure to obtain the titlecompound (56 mg, 0.22 mmol, 107% yield). MS (ESI): mass calcd. forC₁₃H₁₆F₃NO 259.1; m/z found, 260.1 [M+H]⁺.

Intermediate 29:(racemic)-(cis)-3-Methyl-4-(3-(trifluoromethyl)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 3-(trifluoromethyl)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid. MS (ESI): mass calcd. forC₁₃H₁₆F₃N, 243.1; m/z found, 244.1 [M+H]⁺.

Intermediate 30:(racemic)-(cis)-3-Methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 3-methyl-4-(trifluoromethoxy)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid. MS (ESI): mass calcd. forC₁₄H₁₈F₃NO 273.1; m/z found, 274.2 [M+H]⁺.

Intermediate 31:(racemic)-(cis)-3-Methyl-4-(4-(trifluoromethoxy)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 4-(trifluoromethoxy)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid and stirring for 48 hours insteadof overnight. MS (ESI): mass calcd. for C₁₃H₁₆F₃NO 259.1; m/z found,260.0 [M+H]⁺.

Intermediate 32:(racemic)-(cis)-3-Methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 3-fluoro-4-(trifluoromethoxy)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid and stirring for 48 hours insteadof overnight. MS (ESI): mass calcd. for C₁₃H₁₅F₄NO 277.1; m/z found,278.2 [M+H]⁺.

Intermediate 33:(racemic)-(cis)-3-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 4-(trifluoromethyl)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid and stirring the reaction mixturein Step B for 5 days. MS (ESI): mass calcd. for C₁₃H₁₆F₃N, 243.1; m/zfound, 244.1 [M+H]⁺.

Intermediate 34:(racemic)-(cis)-3-Methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine

The title compound was prepared in a manner analogous tocis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)using 3-methyl-4-(trifluoromethyl)phenylboronic acid instead of3-(trifluoromethoxy)phenylboronic acid and stirring the reaction mixturein Step B for 5 days.

Example 1:(2s,4s)-2-(4-(3-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

In an oven-dried pressure vial,(2s,4s)-2-(4-bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Intermediate 11, 31.5 mg, 0.099 mmol) was combined with1-bromo-3-(2,2,2-trifluoroethyl)benzene (25 mg, 0.099 mmol), NiCl₂ (DME)(4.5 mg, 0.020 mmol), 1,10-phenanthroline (7.3 mg, 0.040 mmol), NaBF₄(5.6 mg, 0.050 mmol), and Mn (11 mg, 0.200 mmol). This was taken up inanhydrous MeOH (0.5 mL) and 4-ethylpyridine (5.7 μL, 0.050 mmol) wasadded. The vial was capped, purged with N₂, and heated at 60° C. for 18hours. The mixture was diluted with EtOAc, filtered through Celite®, andconcentrated under reduced pressure. Purification via reverse phase HPLC(5-95% ACN in 20 mM NH₄OH in water) afforded the title compound (23 mg,58% yield). MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found,397.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.30 (t, J=7.6 Hz, 1H), 7.16(dd, J=7.6, 1.7 Hz, 2H), 7.10 (s, 1H), 6.22 (s, 1H), 4.81-4.71 (m, 1H),4.38 (s, 2H), 3.89-3.78 (m, 1H), 3.34 (q, J=10.9 Hz, 2H), 3.12 (td,J=13.1, 2.5 Hz, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.81-2.62 (m, 4H),2.56-2.41 (m, 2H), 1.96-1.87 (m, 2H), 1.70-1.51 (m, 2H).

Example 2:(2s,4s)-2-(4-(3-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using1-bromo-3-fluoro-5-(trifluoromethoxy)benzene instead of1-bromo-3-(2,2,2-trifluoroethyl)benzene. MS (ESI): mass calcd. forC₁₉H₂₀F₄N₂O₄, 416.1; m/z found, 417.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ6.88-6.79 (m, 3H), 6.03 (s, 1H), 4.82-4.74 (m, 1H), 4.38 (s, 2H),3.89-3.79 (m, 1H), 3.17-3.07 (m, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.83-2.61(m, 4H), 2.55-2.42 (m, 2H), 1.98-1.88 (m, 2H), 1.63-1.45 (m, 2H).

Example 3:(2s,4s)-2-(4-(2-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 1 using2-bromo-1-fluoro-4-(trifluoromethoxy)benzene instead of1-bromo-3-(2,2,2-trifluoroethyl)benzene. MS (ESI): mass calcd. forC₁₉H₂₀F₄N₂O₄, 416.1; m/z found, 417.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.11-7.03 (m, 2H), 7.04-6.99 (m, 1H), 5.78 (s, 1H), 4.85-4.73 (m, 1H),4.39 (s, 2H), 3.85 (d, J=13.3 Hz, 1H), 3.20-2.99 (m, 3H), 2.77-2.62 (m,3H), 2.51 (dd, J=12.7, 8.7 Hz, 2H), 1.93 (d, J=13.3 Hz, 2H), 1.70-1.47(m, 2H).

Example 4:(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate. In anoven-dried pressure vial, N-boc-4-bromopiperidine (30 mg, 0.111 mmol)was combined with 1-bromo-2-methyl-4-(trifluoromethyl)benzene (27 mg,0.111 mmol), NiCl₂ (DME) (2.5 mg, 0.011 mmol), 1,10-phenanthroline (4mg, 0.022 mmol), NaBF₄ (6 mg, 0.056 mmol), and Mn (12 mg, 0.223 mmol).This was taken up in anhydrous MeOH (0.6 mL) and 4-ethylpyridine (6.4μL, 0.056 mmol) was added. The vial was capped, purged with N2, andheated at 60° C. for 18 hours. The mixture was diluted with EtOAc,filtered through Celite®, and concentrated under reduced pressure.Purification via FCC on silica (0-15% EtOAc in hexane) afforded thetitle compound (31 mg, 81% yield). MS (ESI): mass calcd. for C₁₈H₂₄F₃NO₂343.2; m/z found, 288.0 [M+2H−tBu]⁺.

Step B: 4-(2-Methyl-4-(trifluoromethyl)phenyl)pieridin-1-ium chloride.To tert-butyl4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (31 mg,0.090 mmol) in MeOH (0.2 mL) was added HCl in 1,4-dioxane (4 M, 0.23mL). This was heated to 45° C. for 1 hour before concentrating underreduced pressure. The title compound was used without furtherpurification in the next step. MS (ESI): mass calcd. for C₁₃H₁₇ClF₃N,279.1; m/z found, 244.1 [M−Cl]⁺.

Step C:(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride was takenup in DMF (0.6 mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 15 mg, 0.089 mmol), DIPEA (47 μL, 0.268 mmol), and HATU(38 mg, 0.098 mmol). This was stirred at room temperature for 16 hours.The reaction mixture was filtered through a PTFE filter with MeOH andpurified via reverse phase HPLC (5-95% ACN in 20 mM NH40H in water) toafford the title compound (30 mg, 85% yield). MS (ESI): mass calcd. forC₂₀H₂₃F₃N₂O₃, 396.2; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.45-7.38 (m, 2H), 7.22 (d, J=7.9 Hz, 1H), 6.22 (s, 1H), 4.91-4.68 (m,1H), 4.39 (s, 2H), 3.96-3.78 (m, 1H), 3.25-2.93 (m, 3H), 2.82-2.59 (m,3H), 2.56-2.43 (m, 2H), 2.41 (s, 3H), 1.90-1.79 (m, 2H), 1.68-1.48 (m,2H).

Example 5:(2s,4s)-2-(4-(4-(Difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(difluoromethyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₂F₂N₂O₃, 364.2; m/z found, 365.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.49-7.42 (m, 2H), 7.31-7.26 (m, 2H), 6.78-6.46 (m, 1H),6.15 (s, 1H), 4.82-4.73 (m, 1H), 4.38 (s, 2H), 3.89-3.78 (m, 1H),3.19-3.08 (m, 1H), 3.08-2.97 (m, 1H), 2.87-2.75 (m, 1H), 2.75-2.62 (m,3H), 2.56-2.42 (m, 2H), 1.98-1.87 (m, 2H), 1.69-1.47 (m, 2H).

Example 6:(2s,4s)-2-(4-(3-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₁F₃N₂O₄, 398.1; m/z found, 399.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.33 (t, J=7.9 Hz, 1H), 7.14-7.04 (m, 2H), 7.02 (p, J=1.5Hz, 1H), 6.28 (s, 1H), 4.81-4.73 (m, 1H), 4.38 (s, 2H), 3.88-3.80 (m,1H), 3.12 (td, J=13.1, 2.5 Hz, 1H), 3.02 (p, J=8.1 Hz, 1H), 2.83-2.60(m, 4H), 2.53-2.42 (m, 2H), 1.98-1.88 (m, 2H), 1.66-1.47 (m, 2H).

Example 7:(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to Example 4 using1-bromo-2-methyl-4-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.14-7.08 (m, 1H), 7.05-6.97 (m, 2H), 6.13 (s, 1H),4.83-4.73 (m, 1H), 4.39 (s, 2H), 3.91-3.79 (m, 1H), 3.19-3.09 (m, 1H),3.09-2.99 (m, 1H), 2.99-2.88 (m, 1H), 2.77-2.62 (m, 3H), 2.55-2.43 (m,2H), 2.36 (s, 3H), 1.89-1.77 (m, 2H), 1.65-1.44 (m, 2H).

Example 8:(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-methyl-1-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.15-7.09 (m, 1H), 7.07-7.02 (m, 1H), 7.02-6.96 (m, 1H),6.24 (s, 1H), 4.80-4.70 (m, 1H), 4.38 (s, 2H), 3.88-3.76 (m, 1H),3.18-2.97 (m, 2H), 2.78-2.60 (m, 4H), 2.53-2.43 (m, 2H), 2.29 (s, 3H),1.95-1.83 (m, 2H), 1.65-1.43 (m, 2H).

Example 9:(2s,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-cyclopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.09-6.99 (m, 4H), 4.78-4.68 (m, 1H), 4.38 (s, 2H), 3.86-3.75(m, 1H), 3.15-2.96 (m, 2H), 2.79-2.60 (m, 4H), 2.52-2.39 (m, 2H),1.94-1.80 (m, 3H), 1.65-1.44 (m, 2H), 0.98-0.88 (m, 2H), 0.69-0.62 (m,2H).

Example 10:(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-methylbenzotrifluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found, 397.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.53 (d, J=8.0 Hz, 1H), 7.10-7.03 (m, 2H), 4.82-4.71 (m,1H), 4.38 (s, 2H), 3.89-3.80 (m, 1H), 3.18-3.07 (m, 1H), 3.07-2.96 (m,1H), 2.83-2.62 (m, 4H), 2.53-2.40 (m, 5H), 1.95-1.85 (m, 2H), 1.67-1.46(m, 2H).

Example 11:(2s,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-isopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₈N₂O₃, 356.2; m/z found, 357.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.20-7.13 (m, 2H), 7.12-7.06 (m, 2H), 6.38 (s, 1H), 4.79-4.68(m, 1H), 4.39 (s, 2H), 3.87-3.73 (m, 1H), 3.17-3.06 (m, 1H), 3.06-2.96(m, 1H), 2.93-2.81 (m, 1H), 2.79-2.61 (m, 4H), 2.53-2.40 (m, 2H),1.98-1.83 (m, 2H), 1.66-1.46 (m, 2H), 1.23 (d, J=6.9 Hz, 6H).

Example 12:(2s,4s)-2-(4-(4-(Difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(difluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₂F₂N₂O₄, 380.2; m/z found, 381.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.20-7.13 (m, 2H), 7.10-7.04 (m, 2H), 6.48 (t, J=74.0 Hz,1H), 5.80 (s, 1H), 4.81-4.71 (m, 1H), 4.38 (s, 2H), 3.87-3.77 (m, 1H),3.17-2.98 (m, 2H), 2.81-2.60 (m, 4H), 2.55-2.44 (m, 2H), 1.96-1.85 (m,2H), 1.65-1.45 (m, 2H).

Example 13:(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2-methylbenzotrifluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found, 397.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.40 (s, 1H), 7.23 (d, J=1.2 Hz, 2H), 6.15 (s, 1H),4.83-4.69 (m, 1H), 4.38 (s, 2H), 3.89-3.78 (m, 1H), 3.19-3.08 (m, 1H),3.08-2.97 (m, 1H), 2.83-2.61 (m, 4H), 2.53-2.40 (m, 5H), 1.95-1.86 (m,2H), 1.66-1.45 (m, 2H).

Example 14:(2s,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-tert-butylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₃₀N₂O₃, 370.2; m/z found, 371.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.28-7.23 (m, 2H), 7.21-7.18 (m, 1H), 7.02-6.97 (m, 1H), 5.93(s, 1H), 4.81-4.73 (m, 1H), 4.39 (s, 2H), 3.86-3.79 (m, 1H), 3.18-3.09(m, 1H), 3.09-2.99 (m, 1H), 2.79-2.61 (m, 4H), 2.54-2.45 (m, 2H),1.97-1.89 (m, 2H), 1.68-1.50 (m, 2H), 1.32 (s, 9H).

Example 15:(2s,4s)-2-(4-(3-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-isopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₈N₂O₃, 356.2; m/z found, 357.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.26-7.21 (m, 1H), 7.10 (dt, J=7.6, 1.4 Hz, 1H), 7.03 (q, J=1.9Hz, 1H), 6.99 (dt, J=7.6, 1.5 Hz, 1H), 6.16 (s, 1H), 4.82-4.73 (m, 1H),4.39 (s, 2H), 3.83 (dq, J=11.4, 2.3 Hz, 1H), 3.12 (td, J=13.1, 2.5 Hz,1H), 3.03 (q, J=8.1 Hz, 1H), 2.88 (hept, J=6.9 Hz, 1H), 2.78-2.62 (m,4H), 2.54-2.44 (m, 2H), 1.96-1.87 (m, 2H), 1.70-1.51 (m, 2H), 1.24 (d,J=6.9 Hz, 6H).

Example 16:(2r,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2-methylbenzotrifluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₅F₃N₂O₂,394.2; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H),7.25-7.19 (m, 2H), 6.04 (s, 1H), 4.83-4.70 (m, 1H), 3.90-3.79 (m, 1H),3.16-2.97 (m, 2H), 2.82-2.71 (m, 1H), 2.71-2.48 (m, 3H), 2.48-2.42 (m,3H), 2.42-2.30 (m, 4H), 2.28-2.18 (m, 2H), 1.95-1.84 (m, 2H), 1.66-1.46(m, 2H).

Example 17:(2r,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-cyclopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₂, 352.2;m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.09-7.04 (m, 2H),7.04-6.99 (m, 2H), 6.13 (s, 1H), 4.80-4.66 (m, 1H), 3.89-3.77 (m, 1H),3.14-2.96 (m, 2H), 2.76-2.48 (m, 4H), 2.42-2.31 (m, 4H), 2.27-2.17 (m,2H), 1.93-1.81 (m, 3H), 1.67-1.44 (m, 2H), 0.99-0.88 (m, 2H), 0.71-0.60(m, 2H).

Example 18:(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-methylbenzotrifluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₅F₃N₂O₂,394.2; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.9Hz, 1H), 7.10-7.03 (m, 2H), 6.18 (s, 1H), 4.83-4.70 (m, 1H), 3.92-3.79(m, 1H), 3.17-2.95 (m, 2H), 2.81-2.70 (m, 1H), 2.70-2.49 (m, 3H),2.50-2.44 (m, 3H), 2.44-2.31 (m, 4H), 2.27-2.19 (m, 2H), 1.94-1.83 (m,2H), 1.68-1.48 (m, 2H).

Example 19:(2s,4s)-2-(4-(2-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-3-fluorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃FN₂O₃, 346.2; m/z found, 347.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.05-6.98 (m, 1H), 6.92-6.88 (m, 1H), 6.88-6.81 (m, 1H), 6.04(s, 1H), 4.80-4.70 (m, 1H), 4.38 (s, 2H), 3.86-3.75 (m, 1H), 3.19-3.09(m, 1H), 3.09-2.95 (m, 2H), 2.76-2.60 (m, 3H), 2.54-2.41 (m, 2H), 2.31(s, 3H), 1.94-1.81 (m, 2H), 1.68-1.48 (m, 2H).

Example 20:(2s,4s)-2-(4-(4-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(2,2,2-trifluoroethyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found, 397.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.26-7.21 (m, 2H), 7.19-7.14 (m, 2H), 5.78 (s, 1H),4.81-4.72 (m, 1H), 4.38 (s, 2H), 3.88-3.78 (m, 1H), 3.41-3.28 (m, 2H),3.17-2.99 (m, 2H), 2.82-2.59 (m, 4H), 2.57-2.43 (m, 2H), 1.97-1.88 (m,2H), 1.68-1.47 (m, 2H).

Example 21:(2s,4s)-2-(4-(3-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-fluorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃FN₂O₃, 346.2; m/z found, 347.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.14-7.07 (m, 1H), 6.87-6.79 (m, 2H), 4.79-4.70 (m, 1H), 4.38(s, 2H), 3.86-3.76 (m, 1H), 3.17-2.97 (m, 2H), 2.77-2.61 (m, 4H),2.53-2.43 (m, 2H), 2.23 (d, J=1.9 Hz, 3H), 1.94-1.85 (m, 2H), 1.62-1.43(m, 2H).

Example 22:(2r,4s)-2-(4-(3-(tert-Butyl)phenyl)pieridine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-tert-butylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₂N₂O₂, 368.2;m/z found, 369.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.22 (m, 2H),7.20 (p, J=1.4 Hz, 1H), 7.02-6.96 (m, 1H), 6.06 (s, 1H), 4.81-4.70 (m,1H), 3.90-3.79 (m, 1H), 3.14-2.98 (m, 2H), 2.81-2.48 (m, 4H), 2.44-2.32(m, 4H), 2.28-2.19 (m, 2H), 1.97-1.86 (m, 2H), 1.69-1.50 (m, 2H), 1.31(s, 9H).

Example 23:(2s,4s)-2-(4-(3-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-cyclopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.22-7.15 (m, 1H), 6.98-6.92 (m, 1H), 6.92-6.88 (m, 2H), 6.28(s, 1H), 4.80-4.70 (m, 1H), 4.39 (s, 2H), 3.87-3.77 (m, 1H), 3.17-3.06(m, 1H), 3.06-2.97 (m, 1H), 2.77-2.60 (m, 4H), 2.52-2.42 (m, 2H),1.95-1.83 (m, 3H), 1.68-1.46 (m, 2H), 1.00-0.91 (m, 2H), 0.73-0.62 (m,2H).

Example 24:(2s,4s)-2-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2,2-difluoro-1,3-benzodioxole instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₀F₂N₂O₅, 394.1; m/z found, 395.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.00-6.95 (m, 1H), 6.90-6.83 (m, 2H), 6.33 (s, 1H),4.82-4.70 (m, 1H), 4.38 (s, 2H), 3.89-3.78 (m, 1H), 3.17-3.07 (m, 1H),3.07-2.95 (m, 1H), 2.80-2.59 (m, 4H), 2.54-2.39 (m, 2H), 1.96-1.85 (m,2H), 1.62-1.42 (m, 2H).

Example 25:(2s,4s)-2-(4-(4-Cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-cyclobutylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.21-7.14 (m, 2H), 7.14-7.07 (m, 2H), 6.06 (s, 1H), 4.80-4.69(m, 1H), 4.38 (s, 2H), 3.86-3.77 (m, 1H), 3.51 (p, J=8.6 Hz, 1H),3.18-2.97 (m, 2H), 2.79-2.60 (m, 4H), 2.55-2.41 (m, 2H), 2.38-2.27 (m,2H), 2.20-1.78 (m, 6H), 1.66-1.47 (m, 2H).

Example 26:(2s,4s)-2-(4-(3-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-(1,1-difluoroethyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₄F₂N₂O₃, 378.2; m/z found, 379.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.40-7.33 (m, 2H), 7.32 (s, 1H), 7.26-7.20 (m, 1H), 6.18(s, 1H), 4.81-4.73 (m, 1H), 4.38 (s, 2H), 3.88-3.80 (m, 1H), 3.13 (td,J=13.1, 2.5 Hz, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.85-2.62 (m, 4H),2.54-2.43 (m, 2H), 1.98-1.84 (m, 5H), 1.69-1.50 (m, 2H).

Example 27:(2s,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(1-methylcyclopropyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.22-7.16 (m, 2H), 7.11-7.05 (m, 2H), 6.12 (s, 1H), 4.80-4.68(m, 1H), 4.38 (s, 2H), 3.86-3.75 (m, 1H), 3.17-2.98 (m, 2H), 2.77-2.61(m, 4H), 2.53-2.43 (m, 2H), 1.95-1.85 (m, 2H), 1.65-1.46 (m, 2H), 1.39(s, 3H), 0.86-0.81 (m, 2H), 0.74-0.69 (m, 2H).

Example 28:(2s,4s)-2-(4-(4-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(1,1-difluoroethyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₄F₂N₂O₃, 378.2; m/z found, 360.2 [M+H−F]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.45 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 6.06 (s,1H), 4.83-4.72 (m, 1H), 4.38 (s, 2H), 3.88-3.79 (m, 1H), 3.13 (td,J=13.1, 2.5 Hz, 1H), 3.04 (p, J=8.1 Hz, 1H), 2.84-2.61 (m, 4H),2.55-2.44 (m, 2H), 1.97-1.85 (m, 5H), 1.67-1.49 (m, 2H).

Example 29:(2s,4s)-2-(4-(3-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using3-bromo-5-fluorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃FN₂O₃, 346.2; m/z found, 347.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 6.79-6.73 (m, 1H), 6.72 (dt, J=9.6, 2.0 Hz, 1H), 6.66 (dt,J=9.9, 2.0 Hz, 1H), 6.44 (s, 1H), 4.78-4.70 (m, 1H), 4.38 (s, 2H),3.86-3.78 (m, 1H), 3.16-2.95 (m, 2H), 2.79-2.60 (m, 4H), 2.53-2.40 (m,2H), 2.32 (s, 3H), 1.97-1.84 (m, 2H), 1.62-1.44 (m, 2H).

Example 30:(2s,4s)-2-(4-(2,3-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2,3-difluoro-4-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₂F₂N₂O₃, 364.2; m/z found, 365.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 6.91-6.84 (m, 1H), 6.81-6.74 (m, 1H), 5.96 (s, 1H),4.80-4.72 (m, 1H), 4.38 (s, 2H), 3.85-3.76 (m, 1H), 3.19-2.96 (m, 3H),2.76-2.62 (m, 3H), 2.55-2.43 (m, 2H), 2.31-2.22 (m, 3H), 1.94-1.83 (m,2H), 1.69-1.48 (m, 2H).

Example 31:(2s,4s)-2-(4-(2,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2,5-difluoro-4-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₂F₂N₂O₃, 364.2; m/z found, 365.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 6.88-6.80 (m, 1H), 6.78 (dd, J=10.1, 6.1 Hz, 1H), 5.88 (s,1H), 4.81-4.70 (m, 1H), 4.38 (s, 2H), 3.86-3.76 (m, 1H), 3.13 (td,J=13.2, 2.6 Hz, 1H), 3.08-2.97 (m, 2H), 2.76-2.58 (m, 3H), 2.55-2.43 (m,2H), 2.22 (d, J=1.9 Hz, 3H), 1.93-1.83 (m, 2H), 1.59-1.42 (m, 2H).

Example 32:(2r,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-isopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₃₀N₂O₂, 354.2;m/z found, 355.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.13 (m, 2H),7.13-7.06 (m, 2H), 6.04 (s, 1H), 4.78-4.70 (m, 1H), 3.88-3.79 (m, 1H),3.14-2.98 (m, 2H), 2.89 (dq, J=13.8, 6.8 Hz, 1H), 2.77-2.50 (m, 4H),2.43-2.33 (m, 4H), 2.27-2.19 (m, 2H), 1.95-1.84 (m, 2H), 1.66-1.47 (m,2H), 1.24 (d, J=6.9 Hz, 6H).

Example 33:(2s,4s)-2-(4-(2-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using3-bromo-4-fluorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃FN₂O₃, 346.2; m/z found, 347.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.01-6.85 (m, 3H), 6.02 (s, 1H), 4.80-4.72 (m, 1H), 4.38 (s,2H), 3.86-3.77 (m, 1H), 3.14 (td, J=13.2, 2.6 Hz, 1H), 3.09-2.98 (m,2H), 2.74-2.63 (m, 3H), 2.56-2.44 (m, 2H), 2.29 (s, 3H), 1.93-1.83 (m,2H), 1.71-1.49 (m, 2H).

Example 34:(2s,4s)-2-(4-(3,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-o-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzenein Step A. MS (ESI): mass calcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.07 (d, J=7.7 Hz, 1H), 6.95 (d, J=1.9Hz, 1H), 6.91 (dd, J=7.7, 2.0 Hz, 1H), 6.42 (d, J=47.7 Hz, 1H),4.79-4.69 (m, 1H), 4.39 (s, 2H), 3.88-3.77 (m, 1H), 3.10 (td, J=13.9,13.5, 2.8 Hz, 1H), 3.01 (q, J=8.3 Hz, 1H), 2.76-2.62 (m, 4H), 2.52-2.42(m, 2H), 2.24 (s, 3H), 2.23 (s, 3H), 1.93-1.84 (m, 2H), 1.66-1.47 (m,2H).

Example 35:(2s,4s)-2-(4-(2,3-Dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to Example 4 using5-bromo-2,3-dihydro-1H-indene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.16 (d, J=7.7 Hz, 1H), 7.05 (s, 1H), 6.95 (dd, J=7.7, 1.7 Hz,1H), 6.11 (s, 1H), 4.79-4.71 (m, 1H), 4.38 (s, 2H), 3.86-3.78 (m, 1H),3.16-2.95 (m, 2H), 2.92-2.83 (m, 4H), 2.77-2.62 (m, 4H), 2.53-2.43 (m,2H), 2.07 (p, J=7.4 Hz, 2H), 1.96-1.85 (m, 2H), 1.67-1.48 (m, 2H).

Example 36:(2s,4s)-2-(4-(3-Chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-chlorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃ClN₂O₃, 362.1; m/z found, 363.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.19-7.12 (m, 2H), 6.96 (dd, J=7.9, 1.8 Hz, 1H), 6.06 (s,1H), 4.79-4.71 (m, 1H), 4.38 (s, 2H), 3.86-3.76 (m, 1H), 3.15-2.97 (m,2H), 2.75-2.61 (m, 4H), 2.53-2.42 (m, 2H), 2.33 (s, 3H), 1.94-1.84 (m,2H), 1.63-1.44 (m, 2H).

Example 37:(2s,4s)-2-(4-(2-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-fluorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃FN₂O₃, 346.2; m/z found, 347.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.10-7.00 (m, 1H), 7.01-6.93 (m, 2H), 5.98 (s, 1H), 4.80-4.70(m, 1H), 4.38 (s, 2H), 3.87-3.74 (m, 1H), 3.20-2.96 (m, 3H), 2.75-2.61(m, 3H), 2.53-2.42 (m, 2H), 2.26 (d, J=2.3 Hz, 3H), 1.96-1.82 (m, 2H),1.65-1.47 (m, 2H).

Example 38:(2s,4s)-2-(4-(3-Isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-isopropoxybenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₈N₂O₄, 372.2; m/z found, 373.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.20 (t, J=7.9 Hz, 1H), 6.76-6.66 (m, 3H), 6.39 (s, 1H),4.77-4.70 (m, 1H), 4.53 (hept, J=6.0 Hz, 1H), 4.38 (s, 2H), 3.85-3.77(m, 1H), 3.10 (td, J=13.1, 2.5 Hz, 1H), 3.01 (p, J=8.2 Hz, 1H),2.78-2.58 (m, 4H), 2.52-2.41 (m, 2H), 1.96-1.89 (m, 2H), 1.65-1.46 (m,2H), 1.32 (d, J=6.1 Hz, 6H).

Example 39:(2r,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(1-methylcyclopropyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2;m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 2H),7.11-7.05 (m, 2H), 6.02 (s, 1H), 63.14-2.98 (m, 2H), 2.76-2.48 (m, 4H),2.43-2.32 (m, 4H), 2.27-2.19 (m, 2H), 1.88 (dt, J=13.4, 3.3 Hz, 2H),1.65-1.46 (m, 2H), 1.39 (s, 3H), 0.86-0.80 (m, 2H), 0.74-0.67 (m, 2H).

Example 40:(2s,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-(1-methylcyclopropyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₂SN₂O₃, 368.2; m/z found, 369.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.22 (t, J=7.6 Hz, 1H), 7.13-7.09 (m, 1H), 7.07 (t, J=1.9 Hz,1H), 6.97 (dt, J=7.6, 1.5 Hz, 1H), 6.19 (s, 1H), 4.79-4.72 (m, 1H), 4.39(s, 2H), 3.87-3.79 (m, 1H), 3.11 (td, J=13.3, 2.6 Hz, 1H), 3.03 (q,J=8.2 Hz, 1H), 2.78-2.61 (m, 4H), 2.54-2.42 (m, 2H), 1.98-1.86 (m, 2H),1.67-1.48 (m, 2H), 1.39 (s, 3H), 0.87-0.81 (m, 2H), 0.75-0.69 (m, 2H).

Example 41:(2r,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-(1-methylcyclopropyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2;m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.22 (t, J=7.6 Hz,1H), 7.11 (dt, J=7.7, 1.5 Hz, 1H), 7.07 (t, J=1.9 Hz, 1H), 6.97 (dt,J=7.6, 1.5 Hz, 1H), 6.13-5.97 (m, 1H), 4.80-4.71 (m, 1H), 3.89-3.80 (m,1H), 3.16-2.98 (m, 2H), 2.78-2.47 (m, 4H), 2.44-2.32 (m, 4H), 2.28-2.19(m, 2H), 1.95-1.85 (m, 2H), 1.67-1.48 (m, 2H), 1.39 (s, 3H), 0.88-0.80(m, 2H), 0.75-0.68 (m, 2H).

Example 42:(2s,4s)-2-(4-(1H-Inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-1H-indene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzenein Step A. MS (ESI): mass calcd. for C₂₁H₂₄N₂O₃, 352.2; m/z found, 353.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J=29.1, 7.7 Hz, 1H), 7.27(dd, J=29.3, 1.6 Hz, 1H), 7.11-6.99 (m, 1H), 6.89-6.81 (m, 1H),6.59-6.51 (m, 1H), 5.91 (s, 1H), 4.82-4.72 (m, 1H), 4.39 (s, 2H),3.87-3.78 (m, 1H), 3.40-3.34 (m, 2H), 3.19-2.98 (m, 2H), 2.79 (td,J=12.0, 2.8 Hz, 1H), 2.76-2.62 (m, 3H), 2.55-2.45 (m, 2H), 1.99-1.88 (m,2H), 1.74-1.50 (m, 2H).

Example 43:(2s,4s)-2-(4-(2,3-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using3-bromo-o-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzenein Step A. MS (ESI): mass calcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.06 (m, 1H), 7.06-7.02 (m, 1H),6.99 (dd, J=7.5, 1.7 Hz, 1H), 5.89 (s, 1H), 4.82-4.73 (m, 1H), 4.38 (s,2H), 3.88-3.79 (m, 1H), 3.15 (td, J=13.1, 2.5 Hz, 1H), 3.09-2.96 (m,2H), 2.75-2.61 (m, 3H), 2.54-2.43 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H),1.90-1.79 (m, 2H), 1.67-1.47 (m, 2H).

Example 44:(2s,4s)-2-(4-(4-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2-fluorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃FN₂O₃, 346.2; m/z found, 347.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.00-6.95 (m, 1H), 6.95-6.89 (m, 2H), 5.97 (s, 1H), 4.79-4.71(m, 1H), 4.38 (s, 2H), 3.86-3.77 (m, 1H), 3.16-2.96 (m, 2H), 2.75-2.60(m, 4H), 2.54-2.44 (m, 2H), 2.27-2.21 (m, 3H), 1.93-1.83 (m, 2H),1.62-1.43 (m, 2H).

Example 45:(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2-tert-butylpyridine instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₉N₃O₃, 371.2; m/z found, 372.2 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d4) δ 8.36-8.31 (m, 1H), 7.63 (dd, J=8.3, 2.4 Hz, 1H), 7.41(dd, J=8.2, 0.8 Hz, 1H), 4.69-4.61 (m, 1H), 4.49 (s, 2H), 4.04-3.96 (m,1H), 3.23-3.09 (m, 2H), 2.88 (tt, J=12.2, 3.7 Hz, 1H), 2.76 (td, J=12.9,2.8 Hz, 1H), 2.65-2.52 (m, 2H), 2.52-2.42 (m, 2H), 1.95-1.83 (m, 2H),1.66-1.51 (m, 2H), 1.34 (s, 9H).

Example 46:(2s,4s)-2-(4-(2-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-chlorobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₈H₂₁ClN₂O₃, 348.1; m/z found, 349.0 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.36 (dd, J=7.8, 1.4 Hz, 1H), 7.25-7.20 (m, 1H), 7.20-7.12(m, 2H), 6.10 (s, 1H), 4.82-4.75 (m, 1H), 4.39 (s, 2H), 3.87-3.80 (m,1H), 3.27 (tt, J=12.1, 3.5 Hz, 1H), 3.17 (td, J=13.1, 2.6 Hz, 1H), 3.04(p, J=8.1 Hz, 1H), 2.78-2.63 (m, 3H), 2.54-2.45 (m, 2H), 2.00-1.87 (m,2H), 1.59 (qd, J=12.6, 4.2 Hz, 1H), 1.48 (qd, J=12.6, 4.2 Hz, 1H).

Example 47:(2s,4s)-2-(4-(2,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-m-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzenein Step A. MS (ESI): mass calcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.03-6.96 (m, 3H), 5.83 (s, 1H),4.81-4.72 (m, 1H), 4.38 (s, 2H), 3.87-3.77 (m, 1H), 3.17-2.99 (m, 2H),2.92 (tt, J=12.1, 3.5 Hz, 1H), 2.76-2.60 (m, 3H), 2.55-2.44 (m, 2H),2.32 (s, 3H), 2.29 (s, 3H), 1.86-1.77 (m, 2H), 1.65-1.46 (m, 2H).

Example 48:(2s,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromodiphenyl ether instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₄H₂₆N₂O₄, 406.2; m/z found, 407.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.36-7.29 (m, 2H), 7.16-7.05 (m, 3H), 7.02-6.92 (m, 4H), 5.78(s, 1H), 4.81-4.70 (m, 1H), 4.38 (s, 2H), 3.87-3.76 (m, 1H), 3.18-2.97(m, 2H), 2.81-2.59 (m, 4H), 2.56-2.42 (m, 2H), 1.98-1.85 (m, 2H),1.65-1.43 (m, 2H).

Example 49:(2s,4s)-2-(4-(3-Methoxy-4-(trifluoromethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-methoxy-1-(trifluoromethyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.49 (d, J=7.9 Hz, 1H), 6.85-6.76 (m, 2H), 6.00 (s, 1H),4.84-4.71 (m, 1H), 4.38 (s, 2H), 3.90 (s, 3H), 3.89-3.79 (m, 1H), 3.13(td, J=13.1, 2.5 Hz, 1H), 3.04 (p, J=8.0 Hz, 1H), 2.85-2.59 (m, 4H),2.56-2.42 (m, 2H), 1.98-1.88 (m, 2H), 1.64-1.45 (m, 2H).

Example 50:(2s,4s)-2-(4-(2-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-cyclopropylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.21-7.10 (m, 3H), 7.05 (dd, J=7.8, 1.9 Hz, 1H), 6.12 (s, 1H),4.84-4.76 (m, 1H), 4.39 (s, 2H), 3.91-3.80 (m, 1H), 3.43 (tt, J=12.1,3.5 Hz, 1H), 3.16 (td, J=13.1, 2.5 Hz, 1H), 3.05 (p, J=8.1 Hz, 1H),2.80-2.63 (m, 3H), 2.54-2.44 (m, 2H), 2.01-1.84 (m, 3H), 1.69-1.51 (m,2H), 0.99-0.89 (m, 2H), 0.71-0.60 (m, 2H).

Example 51:(2r,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromodiphenyl ether instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₅H₂₈N₂O₃, 404.2;m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 2H),7.16-7.12 (m, 2H), 7.12-7.07 (m, 1H), 7.02-6.98 (m, 2H), 6.98-6.91 (m,2H), 5.91 (s, 1H), 4.81-4.71 (m, 1H), 3.91-3.79 (m, 1H), 3.16-2.98 (m,2H), 2.79-2.62 (m, 2H), 2.62-2.48 (m, 2H), 2.45-2.32 (m, 4H), 2.27-2.19(m, 2H), 1.96-1.86 (m, 2H), 1.61-1.45 (m, 2H).

Example 52:(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using3-bromo-2-methylbenzotrifluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found, 397.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.51 (dd, J=7.8, 1.4 Hz, 1H), 7.32 (dd, J=8.0, 1.4 Hz,1H), 7.26 (d, J=15.6 Hz, 1H), 6.22 (s, 1H), 4.84-4.76 (m, 1H), 4.39 (s,2H), 3.91-3.82 (m, 1H), 3.21-2.98 (m, 3H), 2.77-2.64 (m, 3H), 2.54-2.46(m, 2H), 2.44 (d, J=1.6 Hz, 3H), 1.89-1.79 (m, 2H), 1.67-1.48 (m, 2H).

Example 53:(2s,4s)-2-(4-(3-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-phenoxybenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₄H₂₆N₂O₄, 406.2; m/z found, 407.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.37-7.29 (m, 2H), 7.29-7.23 (m, 1H), 7.13-7.07 (m, 1H),7.02-6.96 (m, 2H), 6.92 (dt, J=7.8, 1.3 Hz, 1H), 6.88-6.82 (m, 2H), 5.86(s, 1H), 4.79-4.68 (m, 1H), 4.37 (s, 2H), 3.86-3.75 (m, 1H), 3.15-2.97(m, 2H), 2.79-2.59 (m, 4H), 2.54-2.42 (m, 2H), 1.97-1.87 (m, 2H),1.62-1.46 (m, 2H).

Example 54:(2s,4s)-2-(4-(4-Chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2-chlorotoluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₃ClN₂O₃, 362.1; m/z found, 363.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.26 (d, J=8.2 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.93 (dd,J=8.2, 2.3 Hz, 1H), 6.05 (s, 1H), 4.79-4.71 (m, 1H), 4.38 (s, 2H),3.86-3.75 (m, 1H), 3.16-2.94 (m, 2H), 2.75-2.60 (m, 4H), 2.54-2.43 (m,2H), 2.35 (s, 3H), 1.88 (dq, J=12.9, 2.2 Hz, 2H), 1.63-1.44 (m, 2H).

Example 55:(2s,4s)-2-(4-(2-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-3-methoxybenzotrifluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.19 (d, J=1.1 Hz, 2H), 7.06 (s, 1H), 6.01 (s, 1H),4.80-4.73 (m, 1H), 4.38 (s, 2H), 3.88 (s, 3H), 3.85-3.76 (m, 1H),3.27-3.10 (m, 2H), 3.04 (p, J=8.1 Hz, 1H), 2.75-2.62 (m, 3H), 2.55-2.44(m, 2H), 1.95-1.83 (m, 2H), 1.63-1.44 (m, 2H).

Example 56:(2s,4s)-2-(4-(2-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₁F₃N₂O₄, 398.1; m/z found, 399.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.30-7.20 (m, 4H), 5.92 (s, 1H), 4.82-4.74 (m, 1H), 4.38(s, 2H), 3.87-3.78 (m, 1H), 3.22-3.10 (m, 2H), 3.11-2.99 (m, 1H),2.76-2.62 (m, 3H), 2.56-2.44 (m, 2H), 1.92-1.81 (m, 2H), 1.62-1.44 (m,2H).

Example 57:(2s,4s)-2-(4-([1,1′-Biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using3-bromobiphenyl instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzenein Step A. MS (ESI): mass calcd. for C₂₄H₂₆N₂O₃, 390.2; m/z found, 391.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.54 (m, 2H), 7.48-7.32 (m, 6H),7.17 (dt, J=7.5, 1.5 Hz, 1H), 5.82 (s, 1H), 4.83-4.74 (m, 1H), 4.38 (s,2H), 3.84 (d, J=13.4 Hz, 1H), 3.20-3.10 (m, 1H), 3.10-2.99 (m, 1H), 2.83(tt, J=12.2, 3.6 Hz, 1H), 2.76-2.60 (m, 3H), 2.58-2.44 (m, 2H), 1.98(dd, J=14.3, 3.8 Hz, 2H), 1.76-1.54 (m, 2H).

Example 58:(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-(trifluoromethoxy)anisole instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₅, 428.2; m/z found, 429.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.09-7.01 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.11 (s, 1H),4.79-4.70 (m, 1H), 4.38 (s, 2H), 3.87-3.79 (m, 4H), 3.17-2.96 (m, 2H),2.75-2.61 (m, 4H), 2.54-2.41 (m, 2H), 1.90 (dq, J=12.8, 2.1 Hz, 2H),1.61-1.39 (m, 2H).

Example 59:(2s,4s)-2-(4-(4-(Pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2-(4-bromophenoxy)pyridine instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₃H₂₅N₃O₄, 407.2; m/z found, 408.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.21-8.17 (m, 1H), 7.71-7.65 (m, 1H), 7.23-7.15 (m, 2H),7.12-7.05 (m, 2H), 7.01-6.96 (m, 1H), 6.91 (dt, J=8.3, 0.9 Hz, 1H), 5.78(s, 1H), 4.77 (d, J=13.6 Hz, 1H), 4.38 (s, 2H), 3.83 (d, J=13.3 Hz, 1H),3.18-2.99 (m, 2H), 2.83-2.59 (m, 4H), 2.56-2.43 (m, 2H), 1.94 (d, J=13.2Hz, 2H), 1.70-1.46 (m, 2H).

Example 60:(2s,4s)-2-(4-(4-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-2-chloro-1-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₀ClF₃N₂O₄, 432.1; m/z found, 433.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.41 (d, J=8.3 Hz, 1H), 7.16-7.09 (m, 1H), 7.07 (dd,J=8.4, 2.0 Hz, 1H), 6.06 (s, 1H), 4.82-4.73 (m, 1H), 4.38 (s, 2H),3.89-3.79 (m, 1H), 3.17-3.07 (m, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.82-2.60(m, 4H), 2.53-2.43 (m, 2H), 1.92 (dq, J=12.8, 2.2 Hz, 2H), 1.63-1.43 (m,2H).

Example 61:(2s,4s)-2-(4-(4-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-1-fluoro-2-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₀F₄N₂O₄, 416.1; m/z found, 417.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.18-7.06 (m, 3H), 5.94 (s, 1H), 4.81-4.72 (m, 1H), 4.38(s, 2H), 3.88-3.78 (m, 1H), 3.12 (td, J=13.1, 2.5 Hz, 1H), 3.08-2.97 (m,1H), 2.80-2.57 (m, 4H), 2.55-2.42 (m, 2H), 1.96-1.88 (m, 2H), 1.62-1.43(m, 2H).

Example 62:(2s,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-chloro-3-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₀ClF₃N₂O₄, 432.1; m/z found, 433.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.27 (d, J=7.9 Hz, 1H), 7.22 (dp, J=8.0, 1.4 Hz, 1H), 7.14(dd, J=7.6, 1.7 Hz, 1H), 6.05 (s, 1H), 4.84-4.77 (m, 1H), 4.38 (s, 2H),3.90-3.79 (m, 1H), 3.33 (tt, J=12.1, 3.4 Hz, 1H), 3.18 (td, J=13.0, 2.5Hz, 1H), 3.04 (p, J=8.1 Hz, 1H), 2.77-2.62 (m, 3H), 2.55-2.43 (m, 2H),2.00-1.89 (m, 2H), 1.59 (qd, J=12.7, 4.3 Hz, 1H), 1.47 (qd, J=12.6, 4.1Hz, 1H).

Example 63:(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2-bromo-6-(trifluoromethoxy)toluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.19 (t, J=7.9 Hz, 1H), 7.13-7.04 (m, 2H), 5.98 (s, 1H),4.80 (dt, J=14.2, 2.7 Hz, 1H), 4.39 (s, 2H), 3.90-3.79 (m, 1H), 3.15(td, J=13.1, 2.4 Hz, 1H), 3.10-2.94 (m, 2H), 2.75-2.62 (m, 3H),2.55-2.44 (m, 2H), 2.29 (s, 3H), 1.90-1.80 (m, 2H), 1.63-1.47 (m, 2H).

Example 64:(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-methyl-1-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₅F₃N₂O₃,410.2; m/z found, 411.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.13 (dq,J=8.5, 1.6 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.00 (dd, J=8.4, 2.4 Hz,1H), 5.94 (s, 1H), 4.76 (d, J=13.3 Hz, 1H), 3.85 (d, J=13.5 Hz, 1H),3.14-2.98 (m, 2H), 2.78-2.47 (m, 4H), 2.44-2.32 (m, 4H), 2.29 (s, 3H),2.27-2.19 (m, 2H), 1.88 (d, J=13.3 Hz, 2H), 1.69-1.43 (m, 2H).

Example 65:(2s,4s)-2-(4-(4-Cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-cyclopropyl-2-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₂₈N₂O₃, 368.2; m/z found, 369.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.03-6.97 (m, 1H), 6.91-6.84 (m, 2H), 5.79 (s, 1H), 4.81-4.71(m, 1H), 4.38 (s, 2H), 3.82 (d, J=13.4 Hz, 1H), 3.12 (td, J=13.1, 2.5Hz, 1H), 3.08-3.00 (m, 1H), 2.91 (tt, J=12.1, 3.5 Hz, 1H), 2.74-2.60 (m,3H), 2.54-2.45 (m, 2H), 2.31 (s, 3H), 1.86-1.78 (m, 3H), 1.58-1.45 (m,2H), 0.95-0.89 (m, 2H), 0.68-0.62 (m, 2H).

Example 66:(2s,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-tert-butyl-1-chlorobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₂₉ClN₂O₃, 404.2; m/z found, 405.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.28 (d, J=8.1 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 6.93 (dd,J=8.2, 2.3 Hz, 1H), 5.84 (s, 1H), 4.80-4.73 (m, 1H), 4.38 (s, 2H),3.85-3.78 (m, 1H), 3.12 (td, J=13.1, 2.5 Hz, 1H), 3.04 (tt, J=8.6, 7.5Hz, 1H), 2.76-2.61 (m, 4H), 2.55-2.46 (m, 2H), 1.93-1.86 (m, 2H),1.59-1.48 (m, 2H), 1.47 (s, 9H).

Example 67:(2s,4s)-2-(4-(3-(Difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-difluoromethyoxy-1-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₄F₂N₂O₄, 394.2; m/z found, 395.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.16 (dd, J=7.8, 0.9 Hz, 1H), 6.94 (dd, J=7.8, 1.8 Hz,1H), 6.90-6.87 (m, 1H), 6.47 (t, J=74.2 Hz, 1H), 6.09 (s, 1H), 4.79-4.72(m, 1H), 4.38 (s, 2H), 3.87-3.78 (m, 1H), 3.11 (td, J=13.1, 2.5 Hz, 1H),3.03 (p, J=8.1 Hz, 1H), 2.76-2.61 (m, 4H), 2.52-2.44 (m, 2H), 2.25 (s,3H), 1.94-1.87 (m, 2H), 1.63-1.46 (m, 2H).

Example 68:(2s,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to Example 4 using4-bromo-2-tert-butyl-1-fluorobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₂₉FN₂O₃, 388.2; m/z found, 389.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.07 (dd, J=8.0, 2.2 Hz, 1H), 6.99-6.89 (m, 2H), 5.86 (s, 1H),4.79-4.73 (m, 1H), 4.38 (s, 2H), 3.82 (dt, J=13.5, 2.3 Hz, 1H), 3.11(td, J=13.1, 2.5 Hz, 1H), 3.08-2.99 (m, 1H), 2.77-2.61 (m, 4H),2.54-2.46 (m, 2H), 1.90 (dq, J=13.0, 2.2 Hz, 2H), 1.65-1.46 (m, 2H),1.37 (d, J=1.0 Hz, 9H).

Example 69:(2r,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2-bromo-6-(trifluoromethoxy)toluene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₅F₃N₂O₃,410.2; m/z found, 411.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.19 (t, J=8.0Hz, 1H), 7.12-7.05 (m, 2H), 6.02 (s, 1H), 4.79 (d, J=13.3 Hz, 1H), 3.88(d, J=13.5 Hz, 1H), 3.17-3.09 (m, 1H), 3.06 (t, J=8.4 Hz, 1H), 2.99 (tt,J=12.1, 3.4 Hz, 1H), 2.68 (t, J=13.0 Hz, 1H), 2.57 (q, J=10.1, 9.5 Hz,2H), 2.44-2.34 (m, 4H), 2.29 (s, 3H), 2.27-2.19 (m, 2H), 1.84 (d, J=13.3Hz, 2H), 1.66-1.47 (m, 2H).

Example 70:(2s,4s)-2-(4-(3-Methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-methyl-5-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 6.92 (s, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.10 (s, 1H),4.76 (d, J=13.3 Hz, 1H), 4.38 (s, 2H), 3.83 (d, J=13.5 Hz, 1H),3.16-2.95 (m, 2H), 2.78-2.60 (m, 4H), 2.54-2.43 (m, 2H), 2.35 (s, 3H),1.95-1.87 (m, 2H), 1.64-1.44 (m, 2H).

Example 71:(2s,4s)-2-(4-(4-(Difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-1-(difluoromethoxy)-2-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₄F₂N₂O₄, 394.2; m/z found, 395.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.05-6.94 (m, 3H), 6.46 (t, J=74.3 Hz, 1H), 6.21 (s, 1H),4.75 (d, J=13.1 Hz, 1H), 4.38 (s, 2H), 3.82 (d, J=13.5 Hz, 1H),3.17-2.95 (m, 2H), 2.76-2.60 (m, 4H), 2.54-2.43 (m, 2H), 2.27 (s, 3H),1.95-1.83 (m, 2H), 1.65-1.43 (m, 2H).

Example 72:(2s,4s)-2-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2-bromo-1-methyl-4-(trifluoromethyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found, 397.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.40-7.35 (m, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.27 (d, J=7.7Hz, 1H), 6.02 (s, 1H), 4.85-4.75 (m, 1H), 4.39 (s, 2H), 3.91-3.79 (m,1H), 3.20-3.10 (m, 1H), 3.10-2.95 (m, 2H), 2.79-2.59 (m, 3H), 2.55-2.46(m, 2H), 2.41 (s, 3H), 1.86 (dt, J=14.2, 2.4 Hz, 2H), 1.64-1.50 (m, 2H).

Example 73:(2r,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-tert-butyl-1-chlorobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₁ClN₂O₂,402.2; m/z found, 403.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.27 (d, J=8.1Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 6.93 (dd, J=8.1, 2.2 Hz, 1H), 6.04 (s,1H), 4.75 (s, 1H), 3.85 (d, J=13.0 Hz, 1H), 3.15-2.98 (m, 2H), 2.76-2.61(m, 2H), 2.56 (s, 2H), 2.43-2.31 (m, 4H), 2.29-2.19 (m, 2H), 1.93-1.83(m, 2H), 1.62-1.48 (m, 2H), 1.47 (s, 9H).

Example 74:(2r,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-chloro-3-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₀H₂₂ClF₃N₂O₃,430.1; m/z found, 431.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.26 (m,1H), 7.22 (dp, J=8.2, 1.5 Hz, 1H), 7.14 (dd, J=7.8, 1.6 Hz, 1H), 6.09(s, 1H), 4.80 (s, 1H), 3.87 (s, 1H), 3.32 (tt, J=12.1, 3.4 Hz, 1H), 3.16(s, 1H), 3.05 (p, J=8.4 Hz, 1H), 2.71 (s, 1H), 2.61-2.52 (m, 2H),2.43-2.35 (m, 4H), 2.24 (t, J=7.6 Hz, 2H), 2.01-1.86 (m, 2H), 1.65-1.39(m, 2H).

Example 75:(2s,4s)-2-(4-(4-Cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-cyclopropoxybenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₆N₂O₄, 370.2; m/z found, 371.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.12-7.06 (m, 2H), 7.01-6.96 (m, 2H), 5.97 (s, 1H), 4.78-4.71(m, 1H), 4.38 (s, 2H), 3.81 (dd, J=13.8, 3.4 Hz, 1H), 3.73-3.66 (m, 1H),3.11 (td, J=13.2, 2.5 Hz, 1H), 3.07-2.99 (m, 1H), 2.74-2.62 (m, 4H),2.53-2.44 (m, 2H), 1.94-1.85 (m, 2H), 1.63-1.42 (m, 2H), 0.79-0.72 (m,4H).

Example 76:(2s,4s)-2-(4-(2-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2-fluoro-3-(trifluoromethoxy)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₀F₄N₂O₄, 416.1; m/z found, 417.5 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.23-7.16 (m, 1H), 7.15-7.06 (m, 2H), 5.76 (s, 1H), 4.79(d, J=13.4 Hz, 1H), 4.38 (s, 2H), 3.83 (d, J=13.6 Hz, 1H), 3.22-3.09 (m,2H), 3.09-2.98 (m, 1H), 2.75-2.61 (m, 3H), 2.51 (td, J=8.6, 4.4 Hz, 2H),1.92 (t, J=11.4 Hz, 2H), 1.73-1.60 (m, 2H).

Example 77:(2s,4s)-2-(4-(3-(Pentafluoro-λ⁶-sulfaneyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using3-bromophenylsulfur pentafluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₈H₂₁FSN₂O₃S, 440.1; m/z found, 441.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.64-7.61 (m, 1H), 7.56 (t, J=2.0 Hz, 1H), 7.42 (t, J=7.9Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 5.74 (s, 1H), 4.84-4.75 (m, 1H), 4.38(s, 2H), 3.85 (d, J=13.3 Hz, 1H), 3.14 (td, J=13.1, 2.4 Hz, 1H),3.09-3.01 (m, 1H), 2.84 (tt, J=12.5, 3.8 Hz, 1H), 2.74-2.60 (m, 3H),2.55-2.47 (m, 2H), 1.99-1.91 (m, 2H), 1.67-1.52 (m, 2H).

Example 78:(2s,4s)-2-(4-(4-(Pentafluoro-λ⁶-sulfaneyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromophenylsulfur pentafluoride instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₈H₂₁FSN₂O₃S, 440.1; m/z found, 441.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.73-7.66 (m, 2H), 7.27 (d, J=8.0 Hz, 2H), 6.09 (s, 1H),4.82-4.76 (m, 1H), 4.38 (s, 2H), 3.89-3.80 (m, 1H), 3.14 (td, J=13.1,2.5 Hz, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.82 (tt, J=12.2, 3.6 Hz, 1H),2.75-2.62 (m, 3H), 2.53-2.45 (m, 2H), 1.96-1.89 (m, 2H), 1.66-1.48 (m,2H).

Example 79:(2r,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-tert-butyl-1-fluorobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₁FN₂O₂,386.2; m/z found, 387.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.07 (dd,J=8.0, 2.2 Hz, 1H), 6.99-6.89 (m, 2H), 6.02 (s, 1H), 4.79-4.73 (m, 1H),3.87-3.80 (m, 1H), 3.13-2.99 (m, 2H), 2.75-2.62 (m, 2H), 2.61-2.51 (m,2H), 2.42-2.32 (m, 4H), 2.27-2.20 (m, 2H), 1.93-1.84 (m, 2H), 1.62-1.44(m, 2H), 1.37 (d, J=1.0 Hz, 9H).

Example 80:(2s,4s)-2-(4-(4-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-isobutylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₃₀N₂O₃, 370.2; m/z found, 371.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.08 (s, 4H), 6.21 (s, 1H), 4.74 (d, J=13.2 Hz, 1H), 4.38 (s,2H), 3.82 (d, J=13.5 Hz, 1H), 3.15-3.06 (m, 1H), 3.02 (q, J=8.2 Hz, 1H),2.77-2.63 (m, 4H), 2.53-2.41 (m, 4H), 1.95-1.87 (m, 2H), 1.84 (dt,J=13.5, 6.8 Hz, 1H), 1.66-1.46 (m, 2H), 0.89 (d, J=6.6 Hz, 6H).

Example 81:(racemic)-(2s,4s)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(1-methylcyclopropyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 6) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2;m/z found, 383.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.17 (m, 2H),7.11-7.06 (m, 2H), 6.04 (s, 1H), 4.79-4.71 (m, 1H), 4.52 (q, J=6.5 Hz,1H), 3.83-3.73 (m, 1H), 3.11 (tt, J=13.0, 2.2 Hz, 1H), 3.02-2.92 (m,1H), 2.77-2.59 (m, 4H), 2.48-2.37 (m, 2H), 1.94-1.85 (m, 2H), 1.66-1.49(m, 2H), 1.44 (d, J=6.5 Hz, 3H), 1.39 (s, 3H), 0.86-0.80 (m, 2H),0.74-0.68 (m, 2H).

Example 82:(2s,4s)-2-(4-(3-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2-(3-bromophenyl)propan-2-ol instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₈N₂O₄, 372.2; m/z found, 355.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.31-7.22 (m, 3H), 7.06 (dt, J=7.2, 1.7 Hz, 1H), 6.17 (s, 1H),4.80-4.72 (m, 1H), 4.39 (s, 2H), 3.88-3.79 (m, 1H), 3.12 (td, J=13.1,2.5 Hz, 1H), 3.05 (d, J=11.0 Hz, 2H), 2.81-2.62 (m, 4H), 2.54-2.43 (m,2H), 1.96-1.87 (m, 2H), 1.68-1.53 (m, 2H), 1.51 (s, 6H).

Example 83:(2s,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-isobutylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₃₀N₂O₃, 370.2; m/z found, 371.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.21 (t, J=7.6 Hz, 1H), 7.00 (tt, J=7.3, 1.3 Hz, 2H), 6.95 (t,J=1.8 Hz, 1H), 5.90 (s, 1H), 4.80-4.71 (m, 1H), 4.38 (s, 2H), 3.82 (d,J=13.4 Hz, 1H), 3.17-2.98 (m, 2H), 2.76-2.62 (m, 4H), 2.54-2.41 (m, 4H),1.97-1.88 (m, 2H), 1.83 (dq, J=13.5, 6.8 Hz, 1H), 1.67-1.48 (m, 2H),0.90 (d, J=6.6 Hz, 6H).

Example 84:(2s,4s)-2-(4-(4-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2-(4-bromophenyl)propan-2-ol instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₂₈N₂O₄, 372.2; m/z found, 355.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.38-7.32 (m, 2H), 7.17-7.12 (m, 2H), 5.87 (s, 1H), 4.76 (d,J=13.3 Hz, 1H), 4.38 (s, 2H), 3.82 (d, J=13.4 Hz, 1H), 3.06 (s, 5H),2.79-2.61 (m, 4H), 2.50 (dd, J=12.7, 8.8 Hz, 2H), 1.93 (d, J=12.9 Hz,2H), 1.51 (s, 6H).

Example 85:(2s,4s)-2-(4-(3,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-m-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzenein Step A. MS (ESI): mass calcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 6.86 (s, 1H), 6.79 (s, 2H), 6.32 (d,J=38.7 Hz, 1H), 4.80-4.70 (m, 1H), 4.39 (s, 2H), 3.85-3.77 (m, 1H),3.14-3.06 (m, 1H), 3.02 (pd, J=8.2, 1.5 Hz, 1H), 2.76-2.61 (m, 4H),2.52-2.43 (m, 2H), 2.29 (s, 6H), 1.93-1.86 (m, 2H), 1.65-1.48 (m, 2H).

Example 86:(2s,4s)-2-(4-(2,4-Difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-2,4-difluoro-3-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₂F₂N₂O₃, 364.2; m/z found, 365.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 6.92 (td, J=8.5, 6.2 Hz, 1H), 6.79 (td, J=8.6, 1.5 Hz,1H), 5.86 (s, 1H), 4.82-4.75 (m, 1H), 4.38 (s, 2H), 3.87-3.80 (m, 1H),3.14 (td, J=13.1, 2.6 Hz, 1H), 3.09-3.01 (m, 2H), 2.74-2.62 (m, 3H),2.54-2.45 (m, 2H), 2.18 (t, J=1.9 Hz, 3H), 1.92-1.82 (m, 2H), 1.68-1.47(m, 2H).

Example 87:(2s,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using(4-bromophenyl)trimethylsilane instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₃₀N₂O₃Si, 386.2; m/z found, 387.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 7.51-7.45 (m, 2H), 7.20-7.14 (m, 2H), 6.01 (s, 1H), 4.76(s, 1H), 4.38 (s, 2H), 3.83 (s, 1H), 3.19-3.00 (m, 2H), 2.78-2.62 (m,4H), 2.53-2.45 (m, 2H), 1.96-1.89 (m, 2H), 1.59 (s, 2H), 0.25 (s, 9H).

Example 88:(2s,4s)-2-(4-(4-Fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-fluoro-2,3-dimethylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₅FN₂O₃, 360.2; m/z found, 361.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 6.92 (dd, J=8.7, 5.7 Hz, 1H), 6.84 (t, J=8.9 Hz, 1H), 6.20 (s,1H), 4.81-4.73 (m, 1H), 4.38 (s, 2H), 3.88-3.80 (m, 1H), 3.13 (td,J=13.1, 2.4 Hz, 1H), 3.08-2.91 (m, 2H), 2.77-2.63 (m, 3H), 2.48 (tt,J=9.9, 2.0 Hz, 2H), 2.25 (s, 3H), 2.20 (d, J=2.2 Hz, 3H), 1.86-1.78 (m,2H), 1.62-1.44 (m, 2H).

Example 89:(2s,4s)-2-(4-(2,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using2,5-dimethylbromobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.05 (dd, J=7.6, 1.0 Hz, 1H), 6.93 (d, J=6.9 Hz, 2H), 6.15 (s,1H), 4.82-4.74 (m, 1H), 4.39 (s, 2H), 3.88-3.81 (m, 1H), 3.13 (td,J=13.1, 2.5 Hz, 1H), 3.04 (p, J=8.1 Hz, 1H), 2.93 (tt, J=12.1, 3.5 Hz,1H), 2.78-2.64 (m, 3H), 2.54-2.43 (m, 2H), 2.30 (s, 3H), 2.29 (s, 3H),1.88-1.79 (m, 2H), 1.67-1.48 (m, 2H).

Example 90:(2s,4s)-2-(4-(3-Ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-2-ethyl-1-fluorobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₅FN₂O₃, 360.2; m/z found, 361.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 6.99 (dd, J=7.3, 2.0 Hz, 1H), 6.97-6.90 (m, 2H), 6.14 (s, 1H),4.79-4.71 (m, 1H), 4.38 (s, 2H), 3.86-3.78 (m, 1H), 3.11 (td, J=13.1,2.5 Hz, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.75-2.60 (m, 6H), 2.53-2.44 (m,2H), 1.93-1.86 (m, 2H), 1.63-1.46 (m, 2H), 1.21 (t, J=7.6 Hz, 3H).

Example 91:(2s,4s)-2-(4-(3,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using5-bromo-1,3-difluoro-2-methylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₁₉H₂₂F₂N₂O₃, 364.2; m/z found, 365.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 6.69-6.63 (m, 2H), 5.99 (s, 1H), 4.78-4.72 (m, 1H), 4.38(s, 2H), 3.85-3.79 (m, 1H), 3.10 (td, J=13.1, 2.5 Hz, 1H), 3.07-2.98 (m,1H), 2.75-2.59 (m, 4H), 2.53-2.46 (m, 2H), 2.15 (t, J=1.7 Hz, 3H),1.94-1.85 (m, 2H), 1.59-1.43 (m, 2H).

Example 92:(2S*,4s,8R*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared via separation of(racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 81) by supercritical fluid chromatography (Stationary phase:Whelk O1 SS, 5 μm 250×21 mm; Mobile phase: 30% MeOH with 0.2% TEA, 70%CO₂). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.16 (m, 2H), 7.11-7.06 (m, 2H),5.86 (s, 1H), 4.79-4.72 (m, 1H), 4.51 (q, J=6.5 Hz, 1H), 3.79 (d, J=13.5Hz, 1H), 3.11 (t, J=13.0 Hz, 1H), 2.99 (tt, J=8.8, 6.6 Hz, 1H),2.76-2.55 (m, 4H), 2.48-2.37 (m, 2H), 1.94-1.85 (m, 2H), 1.67-1.48 (m,2H), 1.44 (d, J=6.5 Hz, 3H), 1.39 (s, 3H), 0.86-0.80 (m, 2H), 0.75-0.68(m, 2H).

Example 93:(2R*,4s,8S*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared via separation of(racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 81) by supercritical fluid chromatography (Stationary phase:Whelk O1 SS, 5 μm 250×21 mm; Mobile phase: 30% MeOH with 0.2% TEA, 70%CO₂). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.16 (m, 2H), 7.12-7.06 (m, 2H),6.02 (s, 1H), 4.79-4.72 (m, 1H), 4.52 (q, J=6.5 Hz, 1H), 3.79 (dd,J=13.3, 3.6 Hz, 1H), 3.11 (tt, J=13.0, 2.1 Hz, 1H), 2.98 (tt, J=8.6, 6.9Hz, 1H), 2.76-2.55 (m, 4H), 2.48-2.37 (m, 2H), 1.94-1.85 (m, 2H),1.67-1.48 (m, 2H), 1.45 (d, J=6.5 Hz, 3H), 1.39 (s, 3H), 0.87-0.81 (m,2H), 0.74-0.69 (m, 2H).

Example 94:(2s,4s)-2-(4-(3-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-(trimethylsilyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₁H₃₀N₂O₃Si, 386.2; m/z found, 387.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.39 (dt, J=7.2, 1.3 Hz, 1H), 7.33-7.28 (m, 2H), 7.16 (dt,J=7.6, 1.7 Hz, 1H), 6.01 (s, 1H), 4.82-4.72 (m, 1H), 4.39 (s, 2H),3.87-3.79 (m, 1H), 3.13 (td, J=13.1, 2.5 Hz, 1H), 3.04 (q, J=8.1 Hz,1H), 2.81-2.60 (m, 4H), 2.54-2.44 (m, 2H), 1.96-1.88 (m, 2H), 1.70-1.49(m, 2H), 0.26 (s, 9H).

Example 95:(2r,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using(4-bromophenyl)trimethylsilane instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₃₂N₂O₂Si,384.2; m/z found, 385.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.44 (m,2H), 7.20-7.14 (m, 2H), 5.92 (s, 1H), 4.80-4.70 (m, 1H), 3.85 (d, J=13.3Hz, 1H), 3.16-2.98 (m, 2H), 2.78-2.47 (m, 4H), 2.44-2.31 (m, 4H),2.27-2.20 (m, 2H), 1.91 (d, J=13.4 Hz, 2H), 1.69-1.50 (m, 2H), 0.26 (s,9H).

Example 96:(2r,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-3-isobutylbenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₂N₂O₂, 368.2;m/z found, 369.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.21 (t, J=7.6 Hz,1H), 7.02-6.97 (m, 2H), 6.95 (d, J=1.8 Hz, 1H), 6.08 (s, 1H), 4.79-4.71(m, 1H), 3.88-3.79 (m, 1H), 3.14-2.98 (m, 2H), 2.76-2.51 (m, 4H), 2.45(d, J=7.1 Hz, 2H), 2.43-2.33 (m, 4H), 2.27-2.19 (m, 2H), 1.94-1.76 (m,3H), 1.67-1.48 (m, 2H), 0.89 (d, J=6.6 Hz, 6H).

Example 97:(2s,4s)-2-(4-(4-(tert-Butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-bromo-1-tert-butyl-2-methoxybenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₃H₃₂N₂O₄, 400.2; m/z found, 401.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.20 (dd, J=7.8, 2.5 Hz, 1H), 6.74-6.64 (m, 2H), 6.62-3.07 (m,1H), 4.80-4.72 (m, 1H), 4.39 (s, 2H), 3.88-3.77 (m, 4H), 3.17-2.96 (m,2H), 2.78-2.61 (m, 4H), 2.52-2.42 (m, 2H), 1.97-1.88 (m, 2H), 1.67-1.46(m, 2H), 1.35 (s, 9H).

Example 98:(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using4-methoxy-3-(trifluoromethyl)bromobenzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.36 (d, J=2.3 Hz, 1H), 7.30 (dd, J=8.5, 2.4 Hz, 1H), 6.95(d, J=8.6 Hz, 1H), 6.02 (s, 1H), 4.82-4.71 (m, 1H), 4.38 (s, 2H), 3.88(s, 3H), 3.86-3.79 (m, 1H), 3.17-2.98 (m, 2H), 2.79-2.61 (m, 4H),2.54-2.44 (m, 2H), 1.94-1.86 (m, 2H), 1.63-1.44 (m, 2H).

Example 99:(racemic)-(2s,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(sec-butyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): masscalcd. for C₂₂H₃₀N₂O₃, 370.2; m/z found, 371.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.10 (q, J=8.4 Hz, 4H), 6.05 (s, 1H), 4.78-4.71 (m, 1H), 4.38(s, 2H), 3.85-3.78 (m, 1H), 3.11 (td, J=13.1, 2.5 Hz, 1H), 3.03 (p,J=8.1 Hz, 1H), 2.76-2.63 (m, 4H), 2.57 (hept, J=7.0 Hz, 1H), 2.52-2.43(m, 2H), 1.96-1.88 (m, 2H), 1.65-1.47 (m, 4H), 1.22 (d, J=7.0 Hz, 3H),0.82 (t, J=7.4 Hz, 3H).

Example 100:(racemic)-(2r,4s)-2-(4-(4-(sec-Buty)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 4 using1-bromo-4-(sec-butyl)benzene instead of1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₃H₃₂N₂O₂, 368.2;m/z found, 369.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.14-7.06 (m, 4H),6.09 (s, 1H), 4.78-4.71 (m, 1H), 3.88-3.80 (m, 1H), 3.14-2.99 (m, 2H),2.75-2.61 (m, 2H), 2.61-2.51 (m, 3H), 2.42-2.31 (m, 4H), 2.27-2.19 (m,2H), 1.90 (dt, J=13.5, 3.2 Hz, 2H), 1.65-1.48 (m, 4H), 1.22 (d, J=7.0Hz, 3H), 0.82 (t, J=7.4 Hz, 3H).

Example 101:(2s,4s)-2-(4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 4 using tert-butyl4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate9) instead of tert-butyl4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate in StepB. MS (ESI): mass calcd. for C₁₉H₂₂N₄O₃, 354.2; m/z found, 355.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 11.32 (s, 1H), 8.24-8.19 (m, 1H), 7.85 (dd,J=7.8, 1.5 Hz, 1H), 7.07-7.02 (m, 1H), 6.21-6.18 (m, 1H), 4.73 (d,J=12.9 Hz, 1H), 4.39 (s, 2H), 3.85 (d, J=13.6 Hz, 1H), 3.26-3.15 (m,1H), 3.14-2.97 (m, 2H), 2.90-2.68 (m, 3H), 2.53-2.42 (m, 2H), 2.22-2.12(m, 2H), 1.86-1.64 (m, 3H).

Example 102:(2s,4s)-2-[4-(6-Fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8-azaspiro[3.4]octan-7-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(6-fluorobenzofuran-3-yl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₁FN₂O₄, 372.1; m/z found, 373.1 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.45 (dd, J=8.6, 5.3 Hz, 1H), 7.37 (d,J=1.0 Hz, 1H), 7.19 (dd, J=9.0, 2.3 Hz, 1H), 7.01 (ddd, J=9.4, 8.6, 2.3Hz, 1H), 5.70 (s, 1H), 4.73 (d, J=13.4 Hz, 1H), 4.38 (s, 2H), 3.83 (d,J=13.9 Hz, 1H), 3.19 (t, J=13.0 Hz, 1H), 3.10-2.92 (m, 2H), 2.79 (t,J=12.8 Hz, 1H), 2.66 (d, J=7.3 Hz, 2H), 2.55-2.45 (m, 2H), 2.12 (d,J=13.5 Hz, 2H), 1.65 (dd, J=25.4, 12.0 Hz, 2H).

Example 103:(2s,4s)-2-(4-(4-(Trifluoromethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-trifluoromethylphenyl)piperidine hydrochlorideinstead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-iumchloride. MS (ESI): mass calcd. for C₁₉H₂₁F₃N₂O₃, 382.1; m/z found,383.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=7.8 Hz, 2H), 7.29 (d,J=7.9 Hz, 2H), 6.53 (s, 1H), 4.77 (d, J=11.7 Hz, 1H), 4.38 (s, 2H), 3.86(d, J=12.6 Hz, 1H), 3.21-3.07 (m, 1H), 3.07-2.93 (m, 1H), 2.90-2.60 (m,4H), 2.55-2.38 (m, 2H), 1.92 (d, J=12.2 Hz, 2H), 1.69-1.47 (m, 2H).

Example 104:(2s,4s)-2-(4-(Benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(benzofuran-2-yl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₂N₂O₄, 354.2; m/z found, 355.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.53-7.47 (m, 1H), 7.43-7.38 (m, 1H), 7.25-7.16(m, 2H), 6.39 (t, J=1.0 Hz, 1H), 5.98 (s, 1H), 4.67-4.58 (m, 1H), 4.38(s, 2H), 3.84-3.74 (m, 1H), 3.24-3.13 (m, 1H), 3.08-2.97 (m, 2H),2.90-2.81 (m, 1H), 2.73-2.62 (m, 2H), 2.52-2.44 (m, 2H), 2.20-2.08 (m,2H), 1.77-1.59 (m, 2H).

Example 105:(2s,4s)-2-(4-(Naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(2-naphthyl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₂H₂₄N₂O₃, 364.2; m/z found, 365.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.84-7.75 (m, 3H), 7.63-7.59 (m, 1H), 7.50-7.41(m, 2H), 7.35-7.30 (m, 1H), 5.93 (s, 1H), 4.86-4.74 (m, 1H), 4.39 (s,2H), 3.92-3.80 (m, 1H), 3.25-3.12 (m, 1H), 3.12-3.01 (m, 1H), 2.98-2.85(m, 1H), 2.80-2.62 (m, 3H), 2.58-2.45 (m, 2H), 2.08-1.94 (m, 2H),1.82-1.54 (m, 2H).

Example 106:(2s,4s)-2-(4-(1H-Indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 2-(piperidin-4-yl)-1H-indole instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₃N₃O₃, 353.2; m/z found, 354.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.51 (s, 1H), 7.56-7.50 (m, 1H), 7.35-7.31 (m,1H), 7.15-7.10 (m, 1H), 7.10-7.03 (m, 1H), 6.48 (s, 1H), 6.26-6.21 (m,1H), 4.68 (d, J=13.3 Hz, 1H), 4.41 (s, 2H), 3.82 (d, J=13.6 Hz, 1H),3.22-3.12 (m, 1H), 3.08-2.94 (m, 2H), 2.84-2.66 (m, 3H), 2.56-2.42 (m,2H), 2.11-2.01 (m, 2H), 1.79-1.66 (m, 2H).

Example 107:(2s,4s)-2-(4-(4-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-(trifluoromethoxy)phenyl)piperidine hydrochlorideinstead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-iumchloride. MS (ESI): mass calcd. for C₁₉H₂₁F₃N₂O₄, 398.1; m/z found,399.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.22-7.17 (m, 2H), 7.17-7.13 (m,2H), 6.03 (s, 1H), 4.80-4.74 (m, 1H), 4.38 (s, 2H), 3.87-3.80 (m, 1H),3.12 (td, J=13.1, 2.5 Hz, 1H), 3.03 (p, J=8.1 Hz, 1H), 2.77 (tt, J=12.1,3.6 Hz, 1H), 2.73-2.63 (m, 3H), 2.54-2.45 (m, 2H), 1.94-1.88 (m, 2H),1.64-1.47 (m, 2H).

Example 108:(2s,4s)-2-(4-(4-(Methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-methylsulfanyl-phenyl)piperidine hydrochlorideinstead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-iumchloride. MS (ESI): mass calcd. for C₁₉H₂₄N₂O₃S, 360.2; m/z found, 361.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.26-7.21 (m, 2H), 7.15-7.09 (m, 2H),5.91 (s, 1H), 4.87-4.65 (m, 1H), 4.40 (s, 2H), 3.96-3.72 (m, 1H),3.22-2.99 (m, 2H), 2.80-2.60 (m, 4H), 2.55-2.48 (m, 3H), 2.49 (s, 3H),1.96-1.86 (m, 2H), 1.70-1.64 (m, 1H).

Example 109:(2s,4s)-2-(4-(4-(Dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using N,N-dimethyl-4-(piperidin-4-yl)aniline instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₇N₃O₃, 357.2; m/z found, 358.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.13-7.00 (m, 2H), 6.84-6.61 (m, 2H), 5.90 (s,1H), 4.78-4.69 (m, 1H), 4.38 (s, 2H), 3.85-3.76 (m, 1H), 3.15-3.06 (m,1H), 3.06-2.98 (m, 1H), 2.94 (s, 6H), 2.74-2.61 (m, 4H), 2.55-2.44 (m,2H), 1.93-1.84 (m, 2H), 1.74-1.43 (m, 2H).

Example 110:(2s,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(5-chloro-1-benzofuran-2-yl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₁ClN₂O₄, 388.1; m/z found, 389.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) 7.45 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H),7.21-7.14 (m, 1H), 6.36-6.31 (m, 1H), 6.28 (s, 1H), 4.73-4.51 (m, 1H),4.38 (s, 2H), 3.89-3.72 (m, 1H), 3.26-3.07 (m, 1H), 3.07-2.94 (m, 2H),2.93-2.75 (m, 1H), 2.75-2.61 (m, 2H), 2.55-2.41 (m, 2H), 2.20-2.05 (m,2H), 1.76-1.57 (m, 2H).

Example 111:(2s,4s)-2-(4-Phenylpiperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-phenylpiperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₂N₂O₃, 314.2; m/z found, 315.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.35-7.28 (m, 2H), 7.25-7.13 (m, 3H), 6.29 (s,1H), 4.81-4.69 (m, 1H), 4.39 (s, 2H), 3.90-3.76 (m, 1H), 3.19-3.07 (m,1H), 3.07-2.96 (m, 1H), 2.81-2.60 (m, 4H), 2.53-2.41 (m, 2H), 1.98-1.87(m, 2H), 1.69-1.47 (m, 2H).

Example 112:(2s,4s)-2-(4-(p-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-methylphenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₄N₂O₃, 328.2; m/z found, 329.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.16-7.09 (m, 2H), 7.09-7.03 (m, 2H), 6.41 (s,1H), 4.81-4.67 (m, 1H), 4.39 (s, 2H), 3.87-3.77 (m, 1H), 3.18-3.06 (m,1H), 3.06-2.96 (m, 1H), 2.79-2.59 (m, 4H), 2.53-2.40 (m, 2H), 2.32 (s,3H), 1.97-1.84 (m, 2H), 1.66-1.46 (m, 2H).

Example 113:(2s,4s)-2-(4-(Naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(naphthanlen-1-yl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₂H₂₄N₂O₃, 364.2; m/z found, 365.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.08 (d, J=8.3 Hz, 1H), 7.90-7.84 (m, 1H), 7.74(d, J=8.2 Hz, 1H), 7.57-7.46 (m, 2H), 7.46-7.39 (m, 1H), 7.35-7.28 (m,1H), 6.45 (s, 1H), 4.92-4.77 (m, 1H), 4.39 (s, 2H), 3.98-3.84 (m, 1H),3.64-3.51 (m, 1H), 3.34-3.20 (m, 1H), 3.12-3.00 (m, 1H), 2.92-2.79 (m,1H), 2.79-2.67 (m, 2H), 2.54-2.42 (m, 2H), 2.14-2.02 (m, 2H), 1.84-1.60(m, 2H).

Example 114:(2s,4s)-2-(4-(4-Fluorophenyl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-fluorophenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₁FN₂O₃, 332.2; m/z found, 333.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.17-7.09 (m, 2H), 7.03-6.95 (m, 2H), 6.08 (s,1H), 4.83-4.68 (m, 1H), 4.38 (s, 2H), 3.88-3.76 (m, 1H), 3.19-3.06 (m,1H), 3.06-2.97 (m, 1H), 2.80-2.59 (m, 4H), 2.56-2.43 (m, 2H), 1.97-1.83(m, 2H), 1.65-1.42 (m, 2H).

Example 115:(2s,4s)-2-(4-(3-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(3-chlorophenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₁ClN₂O₃, 348.1; m/z found, 349.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.26-7.12 (m, 3H), 7.08-7.02 (m, 1H), 6.45 (s,1H), 4.84-4.63 (m, 1H), 4.38 (s, 2H), 3.91-3.72 (m, 1H), 3.22-2.93 (m,2H), 2.80-2.56 (m, 4H), 2.55-2.39 (m, 2H), 1.99-1.80 (m, 2H), 1.68-1.42(m, 2H).

Example 116:(2s,4s)-2-(4-(o-Tolyl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(2-methylphenyl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₄N₂O₃, 328.2; m/z found, 329.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.21-7.07 (m, 4H), 6.37 (s, 1H), 4.84-4.72 (m,1H), 4.39 (s, 2H), 3.90-3.79 (m, 1H), 3.19-3.09 (m, 1H), 3.09-2.90 (m,2H), 2.79-2.61 (m, 3H), 2.53-2.42 (m, 2H), 2.35 (s, 3H), 1.90-1.79 (m,2H), 1.66-1.48 (m, 2H).

Example 117:(2s,4s)-2-(4-(4-Ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-ethylphenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.18-7.12 (m, 2H), 7.12-7.06 (m, 2H), 6.23 (s,1H), 4.80-4.68 (m, 1H), 4.39 (s, 2H), 3.88-3.74 (m, 1H), 3.18-2.97 (m,2H), 2.79-2.55 (m, 6H), 2.53-2.40 (m, 2H), 1.96-1.85 (m, 2H), 1.67-1.47(m, 2H), 1.29-1.18 (m, 3H).

Example 118:(2s,4s)-2-(4-(3-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(3-trifluoromethylphenyl)piperidine hydrochlorideinstead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-iumchloride. MS (ESI): mass calcd. for C₁₉H₂₁F₃N₂O₃, 382.1; m/z found,383.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.34 (m, 4H), 5.96 (s, 1H),4.85-4.73 (m, 1H), 4.39 (s, 2H), 3.90-3.79 (m, 1H), 3.20-3.09 (m, 1H),3.09-2.97 (m, 1H), 2.88-2.77 (m, 1H), 2.77-2.61 (m, 3H), 2.56-2.45 (m,2H), 1.99-1.89 (m, 2H), 1.62-1.50 (m, 2H).

Example 119:(2s,4s)-2-(4-(2-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(2-fluorophenyl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₁FN₂O₃, 332.2; m/z found, 333.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.24-7.06 (m, 3H), 7.06-6.98 (m, 1H), 6.11 (s,1H), 4.81-4.72 (m, 1H), 4.38 (s, 2H), 3.88-3.78 (m, 1H), 3.20-2.96 (m,3H), 2.77-2.63 (m, 3H), 2.54-2.42 (m, 2H), 1.96-1.83 (m, 2H), 1.69-1.50(m, 2H).

Example 120:(2s,4s)-2-(4-(3-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(3-fluorophenyl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₁FN₂O₃, 332.2; m/z found, 333.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.31-7.23 (m, 1H), 6.99-6.84 (m, 3H), 5.96 (s,1H), 4.81-4.70 (m, 1H), 4.38 (s, 2H), 3.89-3.77 (m, 1H), 3.19-2.96 (m,2H), 2.82-2.60 (m, 4H), 2.55-2.44 (m, 2H), 1.98-1.87 (m, 2H), 1.61-1.45(m, 2H).

Example 121:(2s,4s)-2-(4-(4-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-chlorophenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₁ClN₂O₃, 348.1; m/z found, 349.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.31-7.27 (m, 2H), 7.14-7.08 (m, 2H), 5.84 (s,1H), 4.80-4.71 (m, 1H), 4.38 (s, 2H), 3.86-3.76 (m, 1H), 3.17-2.98 (m,2H), 2.79-2.60 (m, 4H), 2.55-2.45 (m, 2H), 1.95-1.85 (m, 2H), 1.59-1.44(m, 2H).

Example 122:(2s,4s)-2-(4-(m-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(3-methylphenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₄N₂O₃, 328.2; m/z found, 329.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.23-7.16 (m, 1H), 7.06-7.01 (m, 1H), 7.01-6.94(m, 2H), 6.01 (s, 1H), 4.80-4.69 (m, 1H), 4.38 (s, 2H), 3.87-3.76 (m,1H), 3.17-2.98 (m, 2H), 2.77-2.61 (m, 4H), 2.54-2.43 (m, 2H), 2.34 (s,3H), 1.96-1.85 (m, 2H), 1.65-1.47 (m, 2H).

Example 123:(2s,4s)-2-(4-(4-Methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-methoxyphenyl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₄N₂O₄, 344.2; m/z found, 345.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.13-7.06 (m, 2H), 6.88-6.81 (m, 2H), 6.08 (s,1H), 4.80-4.69 (m, 1H), 4.38 (s, 2H), 3.85-3.78 (m, 1H), 3.79 (s, 3H),3.16-2.97 (m, 2H), 2.76-2.59 (m, 4H), 2.53-2.42 (m, 2H), 1.96-1.84 (m,2H), 1.64-1.43 (m, 2H).

Example 124:(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride insteadof 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₂H₃₀N₂O₃, 370.2; m/z found, 371.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 2H), 7.16-7.07 (m, 2H), 6.00 (s,1H), 4.81-4.70 (m, 1H), 4.38 (s, 2H), 3.87-3.76 (m, 1H), 3.16-2.98 (m,2H), 2.78-2.60 (m, 4H), 2.54-2.42 (m, 2H), 1.98-1.85 (m, 2H), 1.65-1.44(m, 2H), 1.31 (s, 9H).

Example 125:(2r,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-trifluoromethylphenyl)piperidine hydrochlorideinstead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-iumchloride and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₂, 380.2; m/zfound, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=8.0 Hz, 2H),7.29 (d, J=8.0 Hz, 2H), 6.10 (s, 1H), 4.83-4.73 (m, 1H), 3.92-3.82 (m,1H), 3.18-2.99 (m, 2H), 2.87-2.75 (m, 1H), 2.72-2.62 (m, 1H), 2.62-2.50(m, 2H), 2.43-2.33 (m, 4H), 2.27-2.19 (m, 2H), 1.95-1.86 (m, 2H),1.68-1.49 (m, 2H).

Example 126:(2r,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(5-chloro-1-benzofuran-2-yl)piperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride and using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₁H₂₃ClN₂O₃, 386.1; m/zfound, 387.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.42 (m, 1H),7.34-7.27 (m, 1H), 7.21-7.12 (m, 1H), 6.41-5.99 (m, 2H), 4.70-4.55 (m,1H), 3.88-3.76 (m, 1H), 3.22-3.09 (m, 1H), 3.09-2.92 (m, 2H), 2.87-2.74(m, 1H), 2.61-2.48 (m, 2H), 2.43-2.31 (m, 4H), 2.27-2.18 (m, 2H),2.18-2.04 (m, 2H), 1.76-1.55 (m, 2H).

Example 127:(2r,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride insteadof 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride usingand using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₃H₃₂N₂O₂, 368.2; m/zfound, 369.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.36-7.30 (m, 2H),7.15-7.09 (m, 2H), 6.02 (s, 1H), 4.79-4.71 (m, 1H), 3.88-3.79 (m, 1H),3.14-2.99 (m, 2H), 2.76-2.62 (m, 2H), 2.62-2.50 (m, 2H), 2.44-2.32 (m,4H), 2.26-2.20 (m, 2H), 1.95-1.85 (m, 2H), 1.65-1.48 (m, 2H), 1.31 (s,9H).

Example 128:(2s,4s)-2-(4-Methyl-4-phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-methyl-4-phenylpiperidine instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₄N₂O₃, 328.2; m/z found, 329.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.38-7.28 (m, 4H), 7.25-7.19 (m, 1H), 6.09 (s,1H), 4.36 (s, 2H), 3.81-3.73 (m, 1H), 3.54-3.39 (m, 2H), 3.32-3.23 (m,1H), 2.98 (p, J=8.1 Hz, 1H), 2.72-2.55 (m, 2H), 2.51-2.37 (m, 2H),2.20-2.05 (m, 2H), 1.77-1.61 (m, 2H), 1.27 (s, 3H).

Example 129:(2s,4s)-2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 6-chloro-3-(4-piperidinyl)-1,2-benzoisoxazolehydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₀ClN₃O₄, 389.1; m/z found, 390.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.60 (d, J=1.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H),7.31 (dd, J=8.4, 1.7 Hz, 1H), 5.75 (s, 1H), 4.60 (d, J=13.5 Hz, 1H),4.39 (s, 2H), 3.88 (d, J=13.5 Hz, 1H), 3.34 (tt, J=11.0, 3.9 Hz, 1H),3.30-3.18 (m, 1H), 3.11-2.91 (m, 2H), 2.76-2.60 (m, 2H), 2.56-2.46 (m,2H), 2.21-2.09 (m, 2H), 2.01-1.80 (m, 2H).

Example 130:(2s,4s)-2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidinehydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₁ClN₄O₄, 416.1; m/z found, 417.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.04-7.95 (m, 2H), 7.49-7.43 (m, 2H), 5.63 (s,1H), 4.48 (d, J=13.4 Hz, 1H), 4.38 (s, 2H), 3.80 (d, J=14.0 Hz, 1H),3.33-3.19 (m, 2H), 3.09-2.98 (m, 2H), 2.71-2.60 (m, 2H), 2.56-2.47 (m,2H), 2.23-2.14 (m, 2H), 1.97-1.82 (m, 2H).

Example 131:(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride insteadof 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride andusing (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 6) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/zfound, 385.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H),7.14-7.08 (m, 2H), 6.07 (s, 1H), 4.80-4.70 (m, 1H), 4.52 (q, J=6.5 Hz,1H), 3.84-3.73 (m, 1H), 3.18-3.05 (m, 1H), 2.98 (tt, J=8.7, 7.0 Hz, 1H),2.79-2.57 (m, 4H), 2.50-2.36 (m, 2H), 1.92 (dt, J=13.7, 2.2 Hz, 2H),1.67-1.48 (m, 2H), 1.45 (d, J=6.5 Hz, 3H), 1.31 (s, 9H).

Example 132:(2S*,4s,8R*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared via separation of(racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one(Example 131) by chiral supercritical fluid chromatography (Stationaryphase: Lux Cellulose 4, 5 μm 250×21 mm; Mobile phase: 50% MeOH, 50%CO₂). MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.35-7.31 (m, 2H), 7.13-7.09 (m, 2H),5.91 (s, 1H), 4.80-4.72 (m, 1H), 4.51 (q, J=6.5 Hz, 1H), 3.79 (d, J=13.5Hz, 1H), 3.11 (t, J=13.2 Hz, 1H), 2.99 (tt, J=8.7, 6.7 Hz, 1H),2.77-2.58 (m, 4H), 2.47-2.37 (m, 2H), 1.92 (dd, J=13.9, 3.5 Hz, 2H),1.62-1.48 (m, 2H), 1.45 (d, J=6.5 Hz, 3H), 1.31 (s, 9H).

Example 133:(2R*,4s,8S*)-2-4(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared via separation of(racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one(Example 131) by chiral supercritical fluid chromatography (Stationaryphase: Lux Cellulose 4, 5 μm 250×21 mm; Mobile phase: 50% MeOH, 50%CO₂). MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.3[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.30 (m, 2H), 7.14-7.08 (m, 2H),5.99 (s, 1H), 4.80-4.71 (m, 1H), 4.52 (q, J=6.5 Hz, 1H), 3.80 (dd,J=13.8, 3.4 Hz, 1H), 3.11 (tt, J=13.0, 2.4 Hz, 1H), 2.99 (tt, J=8.7, 6.7Hz, 1H), 2.77-2.59 (m, 4H), 2.47-2.37 (m, 2H), 1.92 (dt, J=13.7, 2.4 Hz,2H), 1.67-1.49 (m, 2H), 1.45 (d, J=6.4 Hz, 3H), 1.31 (s, 9H).

Example 134:(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride insteadof 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride andusing(2s,4s)-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 7) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₄H₃₄N₂O₃, 398.3; m/zfound, 399.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.31 (m, 2H),7.15-7.08 (m, 2H), 6.19 (s, 1H), 4.82-4.72 (m, 1H), 3.83-3.73 (m, 1H),3.18-2.99 (m, 2H), 2.80-2.61 (m, 4H), 2.43-2.32 (m, 2H), 1.92 (dt,J=13.5, 3.2 Hz, 2H), 1.70-1.47 (m, 2H), 1.41 (s, 6H), 1.31 (s, 9H).

Example 135:(2s,4s)-2-(4-(4-Chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-chlorophenyl)-4-methyl-piperidine hydrochlorideinstead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-iumchloride. MS (ESI): mass calcd. for C₁₉H₂₃ClN₂O₃, 362.1; m/z found,363.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.28 (m, 2H), 7.26-7.21 (m,2H), 6.22 (s, 1H), 4.36 (s, 2H), 3.78-3.69 (m, 1H), 3.55-3.38 (m, 2H),3.31-3.22 (m, 1H), 2.97 (p, J=8.2 Hz, 1H), 2.71-2.56 (m, 2H), 2.51-2.35(m, 2H), 2.10-1.99 (m, 2H), 1.71-1.62 (m, 2H), 1.25 (s, 3H).

Example 136:(2s,4s)-2-(4-(Benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 2-(4-piperidyl)-1,3-benzothiazole instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₉H₂₁N₃O₃S, 371.1; m/z found, 372.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.97 (dt, J=8.2, 0.9 Hz, 1H), 7.86 (dt, J=8.0,0.9 Hz, 1H), 7.49-7.44 (m, 1H), 7.39-7.34 (m, 1H), 6.19 (s, 1H),4.69-4.60 (m, 1H), 4.38 (s, 2H), 3.89-3.80 (m, 1H), 3.35 (tt, J=11.2,3.9 Hz, 1H), 3.26-3.16 (m, 1H), 3.02 (p, J=8.2 Hz, 1H), 2.94-2.85 (m,1H), 2.75-2.64 (m, 2H), 2.54-2.44 (m, 2H), 2.29-2.18 (m, 2H), 1.92-1.78(m, 2H).

Example 137:(2s,4s)-2-(4-Methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-methyl-4-(p-tolyl)piperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₆N₂O₃, 342.2; m/z found, 343.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.18 (q, J=8.3 Hz, 4H), 5.96-5.85 (m, 1H), 4.36(s, 2H), 3.82-3.73 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.22 (m, 1H),3.04-2.93 (m, 1H), 2.70-2.54 (m, 2H), 2.51-2.38 (m, 2H), 2.33 (s, 3H),2.16-2.05 (m, 2H), 1.72-1.64 (m, 2H), 1.25 (s, 3H).

Example 138:(2s,4s)-2-(4-Fluoro-4-phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 4-fluoro-4-phenylpiperidine hydrochloride instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₁₈H₂₁FN₂O₃, 332.2; m/z found, 333.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.42-7.29 (m, 5H), 6.03 (s, 1H), 4.70-4.62 (m,1H), 4.39 (s, 2H), 3.74-3.66 (m, 1H), 3.50 (td, J=13.2, 2.7 Hz, 1H),3.12-3.01 (m, 2H), 2.76-2.64 (m, 2H), 2.56-2.46 (m, 2H), 2.13-1.78 (m,4H).

Example 139:(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Step C ofExample 4 using 4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine(Intermediate 8) instead of4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS(ESI): mass calcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/z found, 413.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.20-7.15 (m, 1H), 7.03-6.98 (m, 2H), 6.18 (s,1H), 4.80-4.71 (m, 1H), 4.38 (s, 2H), 3.87-3.78 (m, 1H), 3.11 (td,J=13.1, 2.5 Hz, 1H), 3.03 (p, J=8.2 Hz, 1H), 2.78-2.60 (m, 4H),2.51-2.44 (m, 2H), 2.27 (s, 3H), 1.95-1.87 (m, 2H), 1.63-1.46 (m, 2H).

Example 140:(2s,4s)-2-(4-(4-Chlorophenyl-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

TEA (40 μL, 0.280 mmol) was added dropwise to a stirring 0° C. mixtureof 4-(4-chlorophenyl)-4-ethylpiperidine hydrochloride (25.1 mg, 96.4μmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 15.0 mg, 87.6 μmol) and HATU (41.3 mg, 96.4 μmol) inDMA (876 μL). The reaction mixture was allowed to stir at roomtemperature for 14 h and subsequently diluted with water. Purificationby reverse phase HPLC (ACN/H₂O, 0.05% TFA) afforded the title compound(25.3 mg, 67.1 μmol, 77% yield). MS (ESI): mass calcd. for C₂₀H₂₅ClN₂O₃,376.2; m/z found, 377.1 [M+H]⁺. ¹H NMR (500 MHz, Methanol-d4) δ7.39-7.29 (m, 4H), 4.47 (m, 2H), 3.95 (tin, 1H), 3.61 (m, 1H), 3.21-3.02(m, 3H), 2.60-2.34 (m, 4H), 2.24-2.13 (m, 2H), 1.73-1.56 (m, 4H), 0.58(t, J=7.5 Hz, 3H).

Example 141:(racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 3, 20 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol), andDIPEA (60 μL, 0.35 mmol) in DMF (1 mL) was stirred for 10 minutes.Racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate12, 30 mg, 0.13 mmol) was added and the reaction mixture was stirredovernight at r.t. The reaction mixture was purified by reverse phaseHPLC (Gilson, 0-100% ACN/water, NH₄OH modifier) to afford the titlecompound (9.2 mg, 0.24 mmol, 20% yield). MS (ESI): mass calcd. forC₂₃H₃₂N₂O₃, 384.2; m/z found, 385.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.37-7.29 (m, 2H), 7.10-7.02 (m, 2H), 5.83 (d, J=13.3 Hz, 1H), 4.90-4.56(m, 1H), 4.38 (d, J=12.7 Hz, 2H), 3.91-3.58 (m, 1H), 3.46-2.86 (m, 3H),2.77-2.37 (m, 5H), 2.22-2.08 (m, 1H), 2.07-1.93 (m, 1H), 1.71 (d, J=13.5Hz, 1H), 1.31 (s, 9H), 0.70-0.61 (m, 3H).

Example 142:(2s,4S*)-2-((3R*,4R*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141, 54.4 mg) was resolved using chiral supercritical fluidchromatography (Chiralcel OZ column, 70% CO₂, 15% MeOH, 15% iPrOH, 0.2%isopropylamine eluent) to obtain the title compound, (20.4 mg, 0.053mmol, 75% yield, 100% ee). MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2;m/z found, 385.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 2H),7.09-7.04 (m, 2H), 6.43 (s, 1H), 4.86-4.54 (m, 1H), 4.42-4.33 (m, 2H),3.94-3.83 (m, 1H), 3.42-2.85 (m, 4H), 2.83-2.37 (m, 4H), 2.22-1.93 (m,2H), 1.78-1.64 (m, 1H), 1.31 (s, 9H), 0.72-0.58 (m, 3H).

Example 143:(2s,4R*)-2-((3S*,4S*)-4-(4-tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141, 54.4 mg) was resolved using chiral supercritical fluidchromatography (Chiralcel OZ column, 70% CO₂, 15% MeOH, 15% iPrOH, 0.2%isopropylamine eluent) to obtain the title compound (21.7 mg, 0.056, 80%yield, 89% ee). MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found,385.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.28 (m, 2H), 7.09-7.01 (m,2H), 6.66 (s, 1H), 4.86-4.50 (m, 1H), 4.39 (d, J=13.3 Hz, 2H), 3.93-3.85(m, 1H), 3.45-2.86 (m, 3H), 2.83-2.63 (m, 3H), 2.59-2.33 (m, 2H),2.35-1.90 (m, 2H), 1.87-1.60 (m, 1H), 1.31 (s, 9H), 0.65 (d, J=7.0 Hz,3H).

Example 144:(racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₄H₃₄N₂O₂, 382.3; m/zfound, 383.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ7.36-7.31 (m, 2H),7.09-7.05 (m, 2H), 5.86 (d, J=12.2 Hz, 1H), 4.88-4.51 (m, 1H), 4.01-3.58(m, 1H), 3.43-2.83 (m, 4H), 2.70-2.43 (m, 3H), 2.44-2.31 (m, 3H),2.29-2.19 (m, 2H), 2.19-1.94 (m, 2H), 1.70 (s, 1H), 1.31 (s, 9H), 0.66(d, J=7.0 Hz, 3H).

Example 145:(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(4-(tert-butyl)phenyl)-2-methylpiperidine(Intermediate 25) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS(ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.15-7.08 (m, 2H), 6.08-5.70(m, 1H), 5.14-3.56 (m, 2H), 3.38-2.43 (m, 6H), 2.26-1.86 (m, 2H),1.82-1.43 (m, 5H), 1.31 (s, 9H), 1.28-1.16 (m, 3H). Product is a mixtureof diastereomers.

Example 146:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28)instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine(Intermediate 23). MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/zfound, 413.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.29 (m, 1H),7.10-7.06 (m, 2H), 6.98 (s, 1H), 6.22-6.12 (m, 1H), 4.93-4.55 (m, 1H),4.46-4.28 (m, 2H), 3.95-3.61 (m, 1H), 3.53-3.31 (m, 1H), 3.19-2.87 (m,3H), 2.78-2.62 (m, 3H), 2.60-2.40 (m, 2H), 2.24-2.08 (m, 1H), 2.06-1.90(m, 1H), 0.68-0.63 (m, 3H).

Example 147:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine(Intermediate 30) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 24). MS(ESI): mass calcd. for C₂₁H₂₅F₃N₂O₄, 426.2; m/z found, 427.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.16-7.11 (m, 1H), 7.01-6.98 (m, 1H), 6.98-6.94(m, 1H), 6.22 (s, 1H), 4.89-4.58 (m, 1H), 4.42-4.34 (m, 2H), 3.92-3.61(m, 1H), 3.52-3.34 (m, 1H), 3.19-2.83 (m, 3H), 2.78-2.61 (m, 3H),2.60-2.40 (m, 2H), 2.30 (s, 3H), 2.20-2.05 (m, 1H), 2.04-1.88 (m, 1H),0.71-0.59 (m, 3H).

Example 148:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine (Intermediate 29)instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine(Intermediate 23). MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/zfound, 397.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.41 (m, 2H),7.40-7.36 (m, 1H), 7.35-7.32 (m, 1H), 6.54-6.49 (m, 1H), 4.96-4.59 (m,1H), 4.45-4.35 (m, 2H), 4.02-3.59 (m, 1H), 3.53-3.33 (m, 2H), 3.23-2.88(m, 2H), 2.82-2.38 (m, 4H), 2.29-1.95 (m, 2H), 1.95-1.73 (m, 1H),0.68-0.62 (m, 3H).

Example 149:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine (Intermediate 31)instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine(Intermediate 23). MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₄, 412.2; m/zfound, 413.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.22-7.09 (m, 4H),5.85-5.62 (m, 1H), 4.93-4.56 (m, 1H), 4.42-4.33 (m, 2H), 3.96-3.55 (m,1H), 3.42-2.81 (m, 4H), 2.77-2.41 (m, 4H), 2.22-1.88 (m, 2H), 1.79-1.68(m, 1H), 0.68-0.61 (m, 3H).

Example 150:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine(Intermediate 32) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS(ESI): mass calcd. for C₂₀H₂₂F₄N₂O₄, 430.2; m/z found, 431.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.26-7.23 (m, 1H), 7.01-6.90 (m, 2H), 5.76-5.63(m, 1H), 4.89-4.59 (m, 1H), 4.41-4.34 (m, 2H), 3.93-3.62 (m, 1H),3.41-2.86 (m, 4H), 2.73-2.42 (m, 4H), 2.22-1.85 (m, 2H), 1.77-1.66 (m,1H), 0.73-0.60 (m, 3H).

Example 151:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine (Intermediate 33)instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine(Intermediate 23). MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/zfound, 397.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.61-7.57 (m, 2H),7.30-7.24 (m, 2H), 5.81-5.72 (m, 1H), 4.93-4.55 (m, 1H), 4.42-4.27 (m,2H), 3.94-3.63 (m, 1H), 3.46-2.90 (m, 4H), 2.79-2.40 (m, 4H), 2.24-1.94(m, 2H), 1.80-1.67 (m, 1H), 0.72-0.59 (m, 3H).

Example 152:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine(Intermediate 10) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS(ESI): mass calcd. for C₂₁H₂₅F₃N₂O₃, 410.2; m/z found, 411.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.39-7.34 (m, 1H), 7.25-7.22 (m, 1H), 7.21-7.14(m, 1H), 5.84-5.73 (m, 1H), 4.89-4.58 (m, 1H), 4.42-4.30 (m, 2H),3.95-3.58 (m, 1H), 3.43-2.86 (m, 4H), 2.76-2.41 (m, 7H), 2.24-1.95 (m,2H), 1.76-1.69 (m, 1H), 0.68-0.55 (m, 3H).

Example 153:(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine(Intermediate 34) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS(ESI): mass calcd. for C₂₁H₂₅F₃N₂O₃, 410.2; m/z found, 411.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.58-7.43 (m, 1H), 7.07-7.01 (m, 2H), 5.86-5.77(m, 1H), 4.90-4.59 (m, 1H), 4.43-4.32 (m, 2H), 3.94-3.62 (m, 1H),3.43-2.89 (m, 4H), 2.74-2.42 (m, 7H), 2.22-2.09 (m, 1H), 2.07-1.93 (m,1H), 1.78-1.68 (m, 1H), 0.67-0.61 (m, 3H).

Example 154:(racemic)-(2s,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-4-([1,1′-biphenyl]-3-yl)-3-methylpiperidine (Intermediate 24)instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine(Intermediate 23). MS (ESI): mass calcd. for C₂₅H₂₈N₂O₃, 404.2; m/zfound, 405.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.59-7.56 (m, 2H),7.48-7.42 (m, 3H), 7.41-7.32 (m, 3H), 7.14-7.10 (m, 1H), 5.81-5.64 (m,1H), 4.90-4.59 (m, 1H), 4.45-4.28 (m, 2H), 3.94-3.59 (m, 1H), 3.45-2.91(m, 4H), 2.74-2.43 (m, 5H), 2.27-2.01 (m, 1H), 1.83-1.73 (m, 1H),0.78-0.64 (m, 3H).

Example 155:(racemic)-(2r,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using racemiccis-4-([1,1′-biphenyl]-3-yl)-3-methylpiperidine (Intermediate 24)instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine(Intermediate 23) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₆H₃₀N₂O₂, 402.2; m/zfound, 403.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.60-7.55 (m, 2H),7.49-7.33 (m, 6H), 7.15-7.11 (m, 1H), 5.93-5.81 (m, 1H), 4.92-4.58 (m,1H), 3.95-3.65 (m, 1H), 3.42-2.90 (m, 3H), 2.76-2.00 (m, 11H), 1.83-1.74(m, 1H), 0.70 (d, J=7.0 Hz, 3H).

Example 156:(2s,4R*)-2-((2S*,4R*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine(Intermediate 26) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated twice via chiral supercritical fluidchromatography (CHIRALPAK AD-H column, 70% CO₂, 30% MeOH eluent, thenCHIRACEL OJ-H column, 93% CO₂, 7% MeOH eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found,397.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, J=8.1 Hz, 2H), 7.30 (d,J=8.1 Hz, 2H), 6.64 (s, 1H), 4.39 (s, 3H), 3.39 (d, J=98.3 Hz, 1H), 3.01(q, J=8.1 Hz, 1H), 2.84-2.72 (m, 2H), 2.72-2.63 (m, 1H), 2.48 (tdd,J=12.2, 10.3, 3.8 Hz, 2H), 2.25-2.10 (m, 1H), 2.08-1.98 (m, 1H),1.78-1.63 (m, 3H), 1.21 (d, J=6.4 Hz, 3H).

Example 157:(2s,4S*)-2-((2R*,4S*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine(Intermediate 26) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated twice via chiral supercritical fluidchromatography (CHIRALPAK AD-H column, 70% CO₂, 30% MeOH eluent, thenCHIRACEL OJ-H column, 93% CO₂, 7% MeOH eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found,397.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.59-7.53 (m, 2H), 7.30 (d,J=8.1 Hz, 2H), 6.38 (s, 1H), 4.39 (s, 3H), 3.28 (s, 1H), 3.02 (p, J=8.0Hz, 1H), 2.77 (ddt, J=12.1, 7.5, 1.5 Hz, 2H), 2.68-2.63 (m, 1H),2.56-2.45 (m, 2H), 2.24-2.12 (m, 1H), 2.07-1.99 (m, 1H), 1.86-1.64 (m,3H), 1.21 (d, J=6.4 Hz, 3H).

Example 158:(2s,4S*)-2-((2R*,4R*)-2-Methyl-4-(4-(trifluoromethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine(Intermediate 26) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated twice via chiral supercritical fluidchromatography (CHIRALPAK AD-H column, 70% CO₂, 30% MeOH eluent, thenCHIRACEL OJ-H column, 93% CO₂, 7% MeOH eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found,397.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d, J=8.1 Hz, 2H),7.32-7.28 (m, 2H), 6.23-6.10 (m, 1H), 5.12-4.62 (m, 1H), 4.43-4.37 (m,2H), 4.23-3.59 (m, 1H), 3.35-2.84 (m, 3H), 2.80-2.58 (m, 2H), 2.56-2.42(m, 2H), 1.98-1.72 (m, 3H), 1.64-1.50 (m, 1H), 1.41-1.19 (m, 3H).

Example 159:(2s,4R*)-2-((2S*,4S*)-2-Methyl-4-(4-(trifluoromethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine(Intermediate 26) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated twice via chiral supercritical fluidchromatography (CHIRALPAK AD-H column, 70% CO₂, 30% MeOH eluent, thenCHIRACEL OJ-H column, 93% CO₂, 7% MeOH eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₀H₂₃F₃N₂O₃, 396.2; m/z found,397.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d, J=8.0 Hz, 2H), 7.30 (d,J=7.9 Hz, 2H), 6.32-6.14 (m, 1H), 5.16-4.59 (m, 1H), 4.45-4.37 (m, 2H),4.21-3.59 (m, 1H), 3.35-2.84 (m, 3H), 2.81-2.58 (m, 2H), 2.57-2.41 (m,2H), 1.98-1.49 (m, 4H), 1.43-1.18 (m, 3H).

Example 160:(2s,4S*)-2-((3R*,4R*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of racemic(2s,4S)-2-((3R,4R)-4-([1,1′-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 154, 76 mg) was resolved using chiral supercritical fluidchromatography (Lux-3 Cellulose column, 55% CO₂, 45% MeOH eluent) toobtain the title compound (28 mg, 0.053 mmol, 74% yield, 100% ee). MS(ESI): mass calcd. for C₂₅H₂₈N₂O₃, 404.2; m/z found, 405.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.59-7.55 (m, 2H), 7.48-7.31 (m, 7H), 7.14-7.09(m, 1H), 6.43-6.38 (m, 1H), 4.92-4.58 (m, 1H), 4.45-4.27 (m, 2H),3.95-3.62 (m, 1H), 3.46-2.90 (m, 3H), 2.80-2.63 (m, 2H), 2.59-2.37 (m,2H), 2.28-2.15 (m, 1H), 2.13-2.01 (m, 1H), 1.81-1.74 (m, 1H), 0.71-0.67(m, 3H).

Example 161:(2s,4R*)-2-((3S*,4S*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of racemic(2s,4S)-2-((3R,4R)-4-([1,1′-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 154, 76 mg) was resolved using chiral supercritical fluidchromatography (Lux-3 Cellulose column, 55% CO₂, 45% MeOH eluent) toobtain the title compound (28.9 mg, 0.053 mmol, 76% yield, 100% ee). MS(ESI): mass calcd. for C₂₅H₂₈N₂O₃, 404.2; m/z found, 405.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.60-7.55 (m, 2H), 7.47-7.32 (m, 6H), 7.16-7.09(m, 1H), 6.51-6.43 (m, 1H), 4.90-4.60 (m, 1H), 4.45-4.32 (m, 2H),3.96-3.62 (m, 1H), 3.44-2.91 (m, 3H), 2.81-2.64 (m, 3H), 2.60-2.36 (m,2H), 2.29-2.14 (m, 1H), 2.13-2.00 (m, 1H), 1.82-1.74 (m, 1H), 0.75-0.65(m, 3H).

Example 162:(racemic)-(2s,4R)-2-((2S,4S)-4-(3-(tert-Butyl)phenyl-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(3-(tert-butyl)phenyl)-2-methylpiperidine(Intermediate 27) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated via chiral supercritical fluid chromatography (IGcolumn, 40% MeOH, 60% CO₂, 0.1% diethylamine eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.29-7.21 (m, 3H), 7.21-7.18 (m, 1H),7.02-6.97 (m, 1H), 5.88-5.75 (m, 1H), 5.10-4.60 (m, 1H), 4.41-4.28 (m,2H), 4.22-3.55 (m, 1H), 3.37-2.83 (m, 3H), 2.80-2.43 (m, 3H), 1.98-1.76(m, 2H), 1.65-1.47 (m, 2H), 1.35-1.24 (m, 12H).

Example 163:(2s,4R*)*-2-((2S*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 145) was separated by chiral supercritical fluid chromatography(OJ-H column, 15% EtOH, 85% CO₂ eluent) to obtain the title compound. MS(ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.33 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H),6.18 (s, 1H), 4.38 (s, 2H), 3.08-2.98 (m, 1H), 2.80-2.72 (m, 1H),2.71-2.59 (m, 2H), 2.56-2.44 (m, 2H), 2.14 (s, 1H), 2.06-1.92 (m, 1H),1.82-1.63 (m, 5H), 1.31 (s, 9H), 1.19 (d, J=6.4 Hz, 3H).

Example 164:(2s,4S*)-2-((2R*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 145) was separated by chiral supercritical fluid chromatography(OJ-H column, 15% EtOH, 85% CO₂ eluent) to obtain the title compound. MS(ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.15-7.09 (m, 2H), 5.88-5.74(m, 1H), 5.09-4.59 (m, 1H), 4.43-4.34 (m, 2H), 4.19-3.52 (m, 1H),3.32-2.83 (m, 3H), 2.77-2.42 (m, 4H), 1.98-1.69 (m, 3H), 1.57-1.39 (m,1H), 1.37-1.22 (m, 12H).

Example 165:(2s,4S*)-2-((2R*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 145) was separated by chiral supercritical fluid chromatography(OJ-H column, 15% EtOH, 85% CO₂ eluent) to obtain the title compound. MS(ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.36-7.29 (m, 2H), 7.14-7.08 (m, 2H), 6.14 (s,1H), 4.38 (s, 2H), 3.08-2.95 (m, 1H), 2.79-2.73 (m, 1H), 2.72-2.58 (m,2H), 2.56-2.39 (m, 2H), 2.14 (s, 1H), 2.04-1.96 (m, 1H), 1.82-1.63 (m,5H), 1.31 (s, 9H), 1.19 (d, J=6.4 Hz, 3H).

Example 166:(2s,4R*)-2-((2S*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A sample of(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 145) was separated by chiral supercritical fluid chromatography(OJ-H column, 15% EtOH, 85% CO₂ eluent) to obtain the title compound. MS(ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.35-7.32 (m, 2H), 7.15-7.09 (m, 2H), 5.91-5.65(m, 1H), 5.11-4.56 (m, 1H), 4.41-4.35 (m, 2H), 4.19-3.48 (m, 1H),3.34-2.82 (m, 3H), 2.76-2.43 (m, 4H), 1.97-1.72 (m, 3H), 1.58-1.46 (m,1H), 1.35-1.23 (m, 12H).

Example 167:(2s,4R*)-2-((2S*,4R*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(3-(tert-butyl)phenyl)-2-methylpiperidine(Intermediate 27) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated via chiral supercritical fluid chromatography (IGcolumn, 40% MeOH, 60% CO₂, 0.1% diethylamine eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.29-7.15 (m, 3H), 7.02-6.97 (m, 1H),6.22 (s, 1H), 4.38 (s, 2H), 3.49 (d, J=4.2 Hz, 2H), 3.07-2.97 (m, 1H),2.80-2.74 (m, 1H), 2.73-2.60 (m, 2H), 2.57-2.41 (m, 2H), 2.16 (s, 1H),2.04-1.95 (m, 1H), 1.75-1.64 (m, 3H), 1.32 (s, 9H), 1.20 (d, J=6.4 Hz,3H).

Example 168:(2s,4S*)-2-((2R*,4S*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A mixture of diastereomers of the title compound was prepared in amanner analogous to racemic(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 141) using 4-(3-(tert-butyl)phenyl)-2-methylpiperidine(Intermediate 27) instead of racemiccis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). Thismixture was separated via chiral supercritical fluid chromatography (IGcolumn, 40% MeOH, 60% CO₂, 0.1% diethylamine eluent) to yield the titlecompound. MS (ESI): mass calcd. for C₂₃H₃₂N₂O₃, 384.2; m/z found, 385.0[M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.31-7.22 (m, 3H), 7.20-7.17 (m, 1H),7.03-6.90 (m, 1H), 6.11 (s, 1H), 4.39 (d, J=6.0 Hz, 2H), 3.54-3.43 (m,2H), 3.03 (p, J=8.0 Hz, 1H), 2.80-2.59 (m, 3H), 2.50 (tdd, J=12.0, 10.0,3.4 Hz, 1H), 2.16 (s, 1H), 2.06-1.94 (m, 1H), 1.68 (s, 3H), 1.32 (d,J=1.5 Hz, 9H), 1.20 (d, J=6.4 Hz, 3H).

Example 169:(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. In anoven-dried flask under N₂, 2-bromo-6-tert-butylpyridine (144 mg, 0.639mmol) was taken up in anhydrous THF (2.5 mL) and cooled to −78° C. Tothis reaction mixture was added n-BuLi (0.37 mL, 0.590 mmol) and thereaction was stirred at −78° C. for 30 minutes. 1-Boc-4-piperidone (100mg, 0.492 mmol) was added and the reaction mixture, and the reactionmixture was stirred at −78° C. for 1 h. After warming to rt, thereaction mixture was quenched with sat. aq. NH₄Cl and extracted withDCM. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by FCC (0-50% EtOAc inhexanes) provided the title compound (115 mg, 70% yield). MS (ESI): masscalcd. for C₁₉H₃₀N₂O₃, 334.2; m/z found, 335.3 [M+H]⁺.

Step B: tert-Butyl6-(tert-butyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate. To acooled to 0° C. solution of tert-Butyl4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (50 mg,0.149 mmol) in pyridine (0.75 mL) was added DMAP (1.9 mg, 0.0150 mmol)and thionyl chloride (21 μL, 0.299 mmol). The reaction mixture waswarmed to rt and stirred for 2 h. The reaction mixture was quenched withsat. aq. NaHCO₃ and extracted with EtOAc. The organic layers wereconcentrated under reduced pressure to provide the title compound, whichwas used in the next step without further purification. MS (ESI): masscalcd. for C₁₉H₂₈N₂O₂, 316.2; m/z found, 317.3 [M+H]⁺.

Step C: tert-Butyl4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carboxylate. To a solution oftert-butyl6-(tert-butyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (47mg, 0.149 mmol) in EtOH (1.5 mL) was added Pd/C (16 mg, 0.0149 mmol, 10wt. %). The reaction mixture was purged with H₂ and stirred at rt for 16h. The reaction was filtered through Celite® and washed with McOH. Theresulting filtrate was concentrated under reduced pressure to providethe title compound, which used in the next step without furtherpurification. MS (ESI): mass calcd. for C₁₉H₃₀N₂O₂, 318.2; m/z found,319.3 [M+H]⁺.

Step D: 2-(tert-Butyl-6-(piperidin-4-yl)pyridine. A solution oftert-Butyl 4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carboxylate (47mg, 0.148 mmol) in HCl (1.25M in EtOH, 1.2 mL) was stirred at 45° C. for1 h. The reaction was concentrated under reduced pressure and theresulting title compound was used in the next step without furtherpurification. MS (ESI): mass calcd. for C₁₄H₂₂N₂, 218.2; m/z found,219.2 [M+H]⁺.

Step E:(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.To a solution of 2-(tert-Butyl)-6-(piperidin-4-yl)pyridine (37 mg, 0.170mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 26 mg, 0.155 mmol) in DMF (0.70 mL), was added DIPEA(0.10 mL, 0.590 mmol) and HATU (63 mg, 0.162 mmol). The resultingreaction mixture was stirred at rt for 1 h. The reaction mixture wasfiltered through a PTFE filter and purified via RP-HPLC (5-95% ACN in 20mM NH40H in water) to afford the title compound (36 mg, 66% yield). MS(ESI): mass calcd. for C₂₁H₂₉N₃O₃, 371.2; m/z found, 372.3 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.51 (t, J=7.8 Hz, 1H), 7.14 (dd, J=8.0,0.8 Hz, 1H), 6.89 (dd, J=7.6, 0.8 Hz, 1H), 6.28 (s, 1H), 4.69-4.60 (m,1H), 4.38 (s, 2H), 3.87-3.78 (m, 1H), 3.22-3.10 (m, 1H), 3.04 (p, J=8.2Hz, 1H), 2.90 (tt, J=11.3, 3.8 Hz, 1H), 2.87-2.75 (m, 1H), 2.76-2.64 (m,2H), 2.52-2.41 (m, 2H), 2.02-1.93 (m, 2H), 1.82-1.67 (m, 2H), 1.32 (s,9H).

Biological Data

The assay used to measure the in vitro activity of MGL is adapted fromthe assay used for another serine hydrolase (FAAH) described in Wilsonet al., 2003 (A high-throughput-compatible assay for determining theactivity of fatty acid amide hydrolase. Wilson S J, Lovenberg T W,Barbier A J. Anal Biochem. 2003 Jul. 15; 318(2):270-5). The assayconsists of combining endogenously expressed MGL from HeLa cells withtest compounds, adding [glycerol-1,3-³H]-oleoyl glycerol, incubating forone hour, and then measuring the amount of cleaved [1,3-³H]-glycerolthat passes through an activated carbon filter. The amount of cleaved,tritiated glycerol passing through the carbon filter is proportional tothe activity of the MGL enzyme in a particular well/test condition.

Standard conditions for this assay combine 300 nM[Glycerol-1,3-³H]-oleoyl glycerol with human MGL from HeLa cells andtest compounds for one hour, after which the reaction is filteredthrough activated carbon and tritium is measured in the flow through.The test compound concentration in screening mode is 10 μM, while thehighest compound concentration in IC₅₀ assays is determined empirically.MGL is the predominant hydrolase in HeLa cells/cell homogenates.

TABLE 3 MGL IC₅₀ Ex # Compound Name (nM) 1(2s,4s)-2-(4-(3-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)- 167-oxa-5-azaspiro[3.4]octan-6-one; 2(2s,4s)-2-(4-(3-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-23 7-oxa-5-azaspiro[3.4]octan-6-one; 3(2s,4s)-2-(4-(2-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-48 7-oxa-5-azaspiro[3.4]octan-6-one; 4(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-11 7-oxa-5-azaspiro[3.4]octan-6-one; 5(2s,4s)-2-(4-(4-(Difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-27 azaspiro[3,4]octan-6-one; 6(2s,4s)-2-(4-(3-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-12 azaspiro[3.4]octan-6-one; 7(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-14 7-oxa-5-azaspiro[3.4]octan-6-one; 8(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-1.6 7-oxa-5-azaspiro[3.4]octan-6-one; 9(2s,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5- 4.3azaspiro[3.4]octan-6-one; 10(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4.3 7-oxa-5-azaspiro[3.4]octan-6-one; 11(2s,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5- 1.1azaspiro[3.4]octan-6-one; 12(2s,4s)-2-(4-(4-(Difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-53 azaspiro[3.4]octan-6-one; 13(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-2.9 7-oxa-5-azaspiro[3.4]octan-6-one; 14(2s,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- 1.6azaspiro[3.4]octan-6-one; 15(2s,4s)-2-(4-(3-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5- 6.9azaspiro[3.4]octan-6-one; 16(2r,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-23 5-azaspiro[3.4]octan-6-one; 17(2r,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-5- 22azaspiro[3.4]octan-6-one; 18(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-14 5-azaspiro[3.4]octan-6-one; 19(2s,4s)-2-(4-(2-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 19azaspiro[3.4]octan-6-one; 20(2s,4s)-2-(4-(4-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)- 8.27-oxa-5-azaspiro[3.4]octan-6-one; 21(2s,4s)-2-(4-(3-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 37azaspiro[3.4]octan-6-one; 22(2r,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5- 16azaspiro[3.4]octan-6-one; 23(2s,4s)-2-(4-(3-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5- 10azaspiro[3.4]octan-6-one; 24(2s,4s)-2-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-19 7-oxa-5-azaspiro[3.4]octan-6-one; 25(2s,4s)-2-(4-(4-Cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5- 1.6azaspiro[3.4]octan-6-one; 26(2s,4s)-2-(4-(3-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-23 azaspiro[3.4]octan-6-one; 27(2s,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)- 0.57-oxa-5-azaspiro[3.4]octan-6-one; 28(2s,4s)-2-(4-(4-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-5.7 azaspiro[3.4]octan-6-one; 29(2s,4s)-2-(4-(3-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 96azaspiro[3.4]octan-6-one; 30(2s,4s)-2-(4-(2,3-Difluoro-4-methylphenyl)piperidine-1-carbonyl)- 167-oxa-5-azaspiro[3.4]octan-6-one; 31(2s,4s)-2-(4-(2,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)- 307-oxa-5-azaspiro[3.4]octan-6-one; 32(2r,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-5- 6.3azaspiro[3.4]octan-6-one; 33(2s,4s)-2-(4-(2-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-110 azaspiro[3.4]octan-6-one; 34(2s,4s)-2-(4-(3,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5- 14azaspiro[3.4]octan-6-one; 35(2s,4s)-2-(4-(2,3-Dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-5.4 azaspiro[3.4]octan-6-one; 36(2s,4s)-2-(4-(3-Chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 11azaspiro[3.4]octan-6-one; 37(2s,4s)-2-(4-(2-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 32azaspiro[3.4]octan-6-one; 38(2s,4s)-2-(4-(3-Isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5- 26azaspiro[3.4]octan-6-one; 39(2r,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)- 1.15-azaspiro[3.4]octan-6-one; 40(2s,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)- 3.27-oxa-5-azaspiro[3.4]octan-6-one; 41(2r,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)- 195-azaspiro[3.4]octan-6-one; 42(2s,4s)-2-(4-(1H-Inden-5-yl)piperidine-1-carbonyl)-7-oxa-5- 9.2azaspiro[3.4]octan-6-one; 43(2s,4s)-2-(4-(2,3-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5- 35azaspiro[3.4]octan-6-one; 44(2s,4s)-2-(4-(4-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 40azaspiro[3.4]octan-6-one; 45(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-5.0 azaspiro[3.4]octan-6-one; 46(2s,4s)-2-(4-(2-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5- 38azaspiro[3.4]octan-6-one; 47(2s,4s)-2-(4-(2,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5- 37azaspiro[3.4]octan-6-one; 48(2s,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5- 0.7azaspiro[3.4]octan-6-one; 49(2s,4s)-2-(4-(3-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-13 7-oxa-5-azaspiro[3.4]octan-6-one; 50(2s,4s)-2-(4-(2-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5- 94azaspiro[3.4]octan-6-one; 51(2r,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-5- 4.2azaspiro[3.4]octan-6-one; 52(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-18 7-oxa-5-azaspiro[3.4]octan-6-one; 53(2s,4s)-2-(4-(3-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5- 5.2azaspiro[3.4]octan-6-one; 54(2s,4s)-2-(4-(4-Chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5- 13azaspiro[3.4]octan-6-one; 55(2s,4s)-2-(4-(2-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-11 7-oxa-5-azaspiro[3.4]octan-6-one; 56(2s,4s)-2-(4-(2-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)- 1407-oxa-5-azaspiro[3.4]octan-6-one; 57(2s,4s)-2-(4-([1,1′-Biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5- 11azaspiro[3.4]octan-6-one; 58(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethoxy)phenyl)piperidine-l-carbonyl)-17 7-oxa-5-azaspiro[3.4]octan-6-one; 59(2s,4s)-2-(4-(4-(Pyridin-2-yloxy)phenyl)piperidine-l-carbonyl)-7-oxa-5-36 azaspiro[3.4]octan-6-one; 60(2s,4s)-2-(4-(4-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5.7 7-oxa-5-azaspiro[3.4]octan-6-one; 61(2s,4s)-2-(4-(4-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-20 7-oxa-5-azaspiro[3.4]octan-6-one; 62(2s,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-2.3 7-oxa-5-azaspiro[3.4]octan-6-one; 63(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-4.3 7-oxa-5-azaspiro[3.4]octan-6-one; 64(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-24 5-azaspiro[3.4]octan-6-one; 65(2s,4s)-2-(4-(4-Cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)- 107-oxa-5-azaspiro[3.4]octan-6-one; 66(2s,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)- 0.67-oxa-5-azaspiro[3.4]octan-6-one; 67(2s,4s)-2-(4-(3-(Difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-21 7-oxa-5-azaspiro[3.4]octan-6-one; 68(2s,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)- 1.17-oxa-5-azaspiro[3.4]octan-6-one; 69(2r,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-15 5-azaspiro[3.4]octan-6-one; 70(2s,4s)-2-(4-(3-Methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-18 7-oxa-5-azaspiro[3.4]octan-6-one; 71(2s,4s)-2-(4-(4-(Difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-15 7-oxa-5-azaspiro[3.4]octan-6-one; 72(2s,4s)-2-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-280 7-oxa-5-azaspiro[3.4]octan-6-one; 73 (2r,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbony)-5- 3.8azaspiro[3.4]octan-6-one; 74(2r,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-13 5-azaspiro[3.4]octan-6-one; 75(2s,4s)-2-(4-(4-Cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5- 33azaspiro[3.4]octan-6-one; 76(2s,4s)-2-(4-(2-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-6.6 7-oxa-5-azaspiro[3.4]octan-6-one; 77(2s,4s)-2-(4-(3-(Pentafluoro-λ6-sulfaneyl)phenyl)piperidine-1-carbonyl)-10 7-oxa-5-azaspiro[3.4]octan-6-one; 78(2s,4s)-2-(4-(4-(Pentafluoro-λ6-sulfaneyl)phenyl)piperidine-1-carbonyl)- 3.7 7-oxa-5-azaspiro[3.4]octan-6-one; 79(2r,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-5.9 azaspiro[3.4]octan-6-one; 80(2s,4s)-2-(4-(4-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5- 0.5azaspiro[3.4]octan-6-one; 81 (racemic)-(2s,4s)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine- 111-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 82(2s,4s)-2-(4-(3-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)- 507-oxa-5-azaspiro[3.4]octan-6-one; 83(2s,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5- 2.5azaspiro[3.4]octan-6-one; 84(2s,4s)-2-(4-(4-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)- 4.77-oxa-5-azaspiro[3.4]octan-6-one; 85(2s,4s)-2-(4-(3,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5- 94azaspiro[3.4]octan-6-one; 86(2s,4s)-2-(4-(2,4-Difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-14 azaspiro[3.4]octan-6-one; 87(2s,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-0.3 azaspiro[3.4]octan-6-one; 88(2s,4s)-2-(4-(4-Fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-18 azaspiro[3.4]octan-6-one; 89(2s,4s)-2-(4-(2,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5- 560azaspiro[3.4]octan-6-one; 90(2s,4s)-2-(4-(3-Ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5- 14azaspiro[3.4]octan-6-one; 91(2s,4s)-2-(4-(3,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-42 azaspiro[3.4]octan-6-one; 92(2S*,4s,8R*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine- 141-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 93(2R*,4s,8S*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-4.5 1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 94(2s,4s)-2-(4-(3-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-0.7 azaspiro[3.4]octan-6-one; 95(2r,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-5- 2.1azaspiro[3.4]octan-6-one; 96(2r,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-5- 23azaspiro[3.4]octan-6-one; 97(2s,4s)-2-(4-(4-(tert-Butyl)-3-methoxyphenyl)piperidine-1-carbonyl)- 0.47-oxa-5-azaspiro[3.4]octan-6-one; 98(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-14 7-oxa-5-azaspiro[3.4]octan-6-one; 99(racemic)-(2s,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1-carbonyl)- 1.17-oxa-5-azaspiro[3.4]octan-6-one; 100(racemic)-(2r,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1 -carbonyl)- 3.55-azaspiro[3.4]octan-6-one; 101(2s,4s)-2-(4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)- 1107-oxa-5-azaspiro[3.4]octan-6-one; 102(2s,4s)-2-[4-(6-Fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8- 11azaspiro[3.4]octan-7-one; 103(2s,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-15 azaspiro[3.4]octan-6-one; 104(2s,4s)-2-(4-(Benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5- 6.6azaspiro[3.4]octan-6-one; 105(2s,4s)-2-(4-(Naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5- 10azaspiro[3.4]octan-6-one; 106(2s,4s)-2-(4-(1H-Indol-2-yl)piperidine-1-carbonyl)-7-oxa-5- 110azaspiro[3.4]octan-6-one; 107(2s,4s)-2-(4-(4-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-14 azaspiro[3.4]octan-6-one; 108(2s,4s)-2-(4-(4-(Methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5- 16azaspiro[3.4]octan-6-one; 109(2s,4s)-2-(4-(4-(Dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5- 23azaspiro[3.4]octan-6-one; 110(2s,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-3.9 azaspiro[3.4]octan-6-one; 111(2s,4s)-2-(4-Phenylpiperidine-1-carbonyl)-7-oxa-5- 98azaspiro[3.4]octan-6-one; 112(2s,4s)-2-(4-(p-Tolyl)piperidine-1-carbonyl)-7-oxa-5- 42azaspiro[3.4]octan-6-one; 113(2s,4s)-2-(4-(Naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5- 19azaspiro[3.4]octan-6-one; 114(2s,4s)-2-(4-(4-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5- 170azaspiro[3.4]octan-6-one; 115(2s,4s)-2-(4-(3-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5- 48azaspiro[3.4]octan-6-one; 116(2s,4s)-2-(4-(o-Tolyl)piperidine-1-carbonyl)-7-oxa-5- 230azaspiro[3.4]octan-6-one; 117(2s,4s)-2-(4-(4-Ethylphenyl)piperidine-1-carbonyl)-7-oxa-5- 8.2azaspiro[3.4]octan-6-one; 118(2s,4s)-2-(4-(3-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-18 azaspiro[3.4]octan-6-one; 119(2s,4s)-2-(4-(2-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5- 66azaspiro[3.4]octan-6-one; 120(2s,4s)-2-(4-(3-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5- 100azaspiro[3.4]octan-6-one; 121(2s,4s)-2-(4-(4-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5- 23azaspiro[3.4]octan-6-one; 122(2s,4s)-2-(4-(m-Tolyl)piperidine-1-carbonyl)-7-oxa-5- 82azaspiro[3.4]octan-6-one; 123(2s,4s)-2-(4-(4-Methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5- 98azaspiro[3.4]octan-6-one; 124(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- 0.2azaspiro[3.4]octan-6-one; 125(2r,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-5- 95azaspiro[3.4]octan-6-one; 126(2r,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5- 32azaspiro[3.4]octan-6-one; 127(2r,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5- 0.9azaspiro[3.4]octan-6-one; 128(2s,4s)-2-(4-Methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5- 89azaspiro[3.4]octan-6-one; 129(2s,4s)-2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)- 387-oxa-5-azaspiro[3.4]octan-6-one; 130(2s,4s)-2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-10 7-oxa-5-azaspiro[3.4]octan-6-one; 131(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)- 4.58-methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 132(2S*,4s,8R*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8- 6.3methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 133(2R*,4s,8S*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8- 2.4methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 134(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8,8- 200dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one; 135(2s,4s)-2-(4-(4-Chlorophenyl)-4-methylpiperidine-1-carbonyl)-7- 11oxa-5-azaspiro[3.4]octan-6-one; 136(2s,4s)-2-(4-(Benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5- 120azaspiro[3.4]octan-6-one; 137(2s,4s)-2-(4-Methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5- 14azaspiro[3.4]octan-6-one; 138(2s,4s)-2-(4-Fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5- 340azaspiro[3.4]octan-6-one; 139 (2s,4s)-2-(4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-4.7 7-oxa-5-azaspiro[3.4]octan-6-one; 140(2s,4s)-2-(4-(4-Chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5- 57azaspiro[3.4]octan-6-one; 141(racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3- 0.2methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 142(2s,4S*)-2-((3R*,4R*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine- 0.41-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 143(2s,4R*)-2-((3S*,4S*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine- 0.31-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 144(racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3- 2.5methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 145(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1- 0.3carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 146(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-9.4 1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 147(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)4.7 piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 148(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3- 24(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 149(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-15 1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 150(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-fluoro-4- 8.2(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 151(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4- 24(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 152(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-methyl-3- 2.5(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 153(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4- 3.7(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 154(racemic)-(2s,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3- 1.2methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 155(racemic)-(2r,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3- 10methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; 156(2s,4R*)-2-((2S*,4R*)-2-Methyl-4-(4- 47(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 157 (2s,4S*)-2-((2R*,4S*)-2-Methyl-4-(4- 12(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 158 (2s,4S*)-2-((2R*,4R*)-2-Methyl-4-(4- 280(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 159 (2s,4R*)-2-((2S*,4S*)-2-Methyl-4-(4- 89(trifluoromethyl)phenyl)piperidine-l-carbonyl)-7-oxa-5-azaspirof3.4]octan-6-one; 160(2s,4S*)-2-((3R*,4R*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine- 7.91-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 161(2s,4R*)-2-((3S*,4S*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine- 1.51-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 162(racemic)-(2s,4R)-2-((2S,4S)-4-(3-(tert-Butyl)phenyl)-2- 2.5methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 163(2s,4R*)-2-((2S*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine- 0.21-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 164(2s,4S*)-2-((2R*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine- 251-carbonyl)-7-oxa-5-azaspiro[3.4] octan-6-one; 165(2s,4S*)-2-((2R*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine- 0.3 1-carbonyl)-7-oxa-5 -azaspiro[3.4] octan-6-one; 166(2s,4R*)-2-((2S*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine- 191-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 167(2s,4R*)-2-((2S*,4R*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine- 121-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 168(2s,4S*)-2-((2R*,4S*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine- 4.21-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and 169(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-2-yl)piperidine-1-carbonyl)-7- 5.7oxa-5-azaspiro[3.4]octan-6-one.

1. A compound of Formula (I):

wherein X is CH₂ or O; R^(2a) and R^(2b) are each independently selectedfrom H and C₁₋₄alkyl; R³ is selected from: (i) phenyl, benzyl, ormonocyclic heteroaryl, each optionally substituted with one, two, orthree substituents selected from: halo, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkyl-OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SC₁₋₆alkyl, SF₅, Si(CH₃)₃,NR^(a)R^(b), C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl, phenyl, O-phenyl, andO-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is optionallysubstituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl, or halo groups; ortwo adjacent ring substituents on the phenyl, benzyl, or monocyclicheteroaryl, taken together with the atoms to which they are attachedform a fused monocyclic C₅₋₆cycloalkyl or heterocycloalkyl ring, eachring optionally substituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl, orhalo groups; wherein R^(a) and R^(b) are each independently H orC₁₋₄alkyl; (ii) a bicyclic heteroaryl optionally substituted withC₁₋₄alkyl or halo; and (iii) C₃₋₆alkyl or C₃₋₆cycloalkyl optionallysubstituted with C₁₋₄alkyl, C₁₋₄haloalkyl, or halo; R⁴ is selected from:H, F, and C₁₋₃alkyl; and R^(5a) and R^(5b) are each independentlyselected from H and CH₃; or a pharmaceutically acceptable salt, isotope,N-oxide, solvate, or stereoisomer thereof.
 2. The compound of claim 1,wherein R³ is selected from:

(a) phenyl; phenyl substituted with one, two or three members eachindependently selected from: halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C(CH₃)₂OH,OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅, Si(CH₃)₃, N(CH₃)₂,C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl, phenyl, O-phenyl, O-pyridyl andC₃₋₆cycloalkyl substituted with CH₃; and (b) pyridyl substituted withC₁₋₆alkyl; naphthyl;


3. The compound of claim 1, wherein X is CH₂.
 4. The compound of claim1, wherein X is O.
 5. The compound of claim 1, wherein R^(2a) and R^(2b)are each H.
 6. The compound of claim 1, wherein R^(2a) and R^(2b) areeach CH₃.
 7. The compound of claim 1, wherein R^(2a) is H and R^(2b) isCH₃.
 8. The compound of claim 1, wherein R³ is phenyl; or phenylsubstituted with one, two or three members each independently selectedfrom: Cl, F, C₁₋₆alkyl, C₁₋₆haloalkyl, C(CH₃)₂OH, OC₁₋₆alkyl,OC₁₋₆haloalkyl, SCH₃, Si(CH₃)₃, SF₅, N(CH₃)₂, C₃₋₆cycloalkyl,C₃₋₆cycloalkyl substituted with CH₃, OC₃₋₆cycloalkyl, phenyl, O-phenyl,and O-pyridyl.
 9. The compound of claim 8, wherein R³ is phenylsubstituted with one, two or three members each independently selectedfrom: halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃,SF₅, and Si(CH₃)₃.
 10. The compound of claim 1, wherein R³ is:


11. The compound of claim 8, wherein R³ is 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or3-(1-methylcyclopropyl)phenyl.
 12. The compound of claim 1, wherein R⁴is H, F, CH₃ or CH₂CH₃.
 13. (canceled)
 14. The compound of claim 1,wherein R^(5a) and R^(5b) are each H.
 15. The compound of claim 1,wherein R^(5a) is CH₃ and R^(5b) is H or R^(5a) is H and R^(5b) is CH₃.16. (canceled)
 17. The compound of claim 1, wherein

18-21. (canceled)
 22. A compound selected from:(2s,4s)-2-(4-(3-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-Cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(2,2,2-Trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(1,1-Difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,3-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-Isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,3-Dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-(1-Methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(1H-Inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,3-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,4-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-Phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-([1,1′-Biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-Methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(Difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(2-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-(tert-Butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(2-Chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(Pentafluoro-λ6-sulfaneyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Pentafluoro-λ6-sulfaneyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-(tert-Butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4s)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(2-Hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,4-Difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2,5-Dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3,5-Difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2S*,4s,8R*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2R*,4s,8S*)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-(Trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(3-Isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(tert-Butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2r,4s)-2-(4-(4-(sec-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[4-(6-Fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8-azaspiro[3.4]octan-7-one;(2s,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(Benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(Naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(1H-Indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(Dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-Phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(p-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(Naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(o-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(2-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-Fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(m-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-(Trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(5-Chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-Methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(6-Chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one;(2S*,4s,8R*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one;(2R*,4s,8S*)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(Benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-Methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-Fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(4-(4-Chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((3R*,4R*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((31S*,4S*)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-Butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4s)-2-(4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-3-Methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2r,4S)-2-((3R,4R)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((2S*,4R*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((2R*,4S*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((2R*,4R*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((2S*,4S*)-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((3R*,4R*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((3S*,4S*)-4-([1,1′-Biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(racemic)-(2s,4R)-2-((2S,4S)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((2S*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((2R*,4R*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((2R*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((2S*,4S*)-4-(4-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((2S*,4R*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4S*)-2-((2R*,4S*)-4-(3-(tert-Butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and(2s,4s)-2-(4-(6-(tert-Butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.
 23. (canceled)
 24. The compound of claim 1,having the structure of Formula (IA):

wherein R³ is selected from: (a) phenyl substituted with one or twomembers each independently selected from: halo, C₁₋₆alkyl,C₁₋₆haloalkyl, OC₁₋₆haloalkyl, Si(CH₃)₃, C₃₋₆cycloalkyl, phenyl,O-phenyl, and C₃₋₆cycloalkyl substituted with CH₃; and (b)

 and R^(5b) is H or CH₃; or a pharmaceutically acceptable salt, isotope,N-oxide, solvate, or stereoisomer thereof.
 25. The compound of claim 1,having the structure of Formula (IB):

wherein R^(2a) and R^(2b) are each independently selected from H andCH₃; R³ is selected from: (a) phenyl; phenyl substituted with one, twoor three members each independently selected from: Cl, F, C₁₋₆alkyl,C₁₋₆haloalkyl, C(CH₃)₂OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅,Si(CH₃)₃, N(CH₃)₂, cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl,O-phenyl, O-pyridyl and

 and (b)

R⁴ is selected from: H, F, CH₃ and CH₂CH₃; R^(5a) is H or CH₃; andR^(5b) is H or CH₃; or a pharmaceutically acceptable salt, isotope,N-oxide, solvate, or stereoisomer thereof.
 26. The compound of claim 1,having the structure of Formula (IC):

wherein X is CH₂ or O; and Ring A is selected from:

or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, orstereoisomer thereof.
 27. The compound of claim 1, having the structureof Formula (ID):

wherein X is CH₂ or O; R^(2a) and R^(2b) are each independently selectedfrom H and CH₃; R^(b) is selected from: Cl, F, C₁₋₆alkyl, C₁₋₆haloalkyl,C(CH₃)₂OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅, Si(CH₃)₃, N(CH₃)₂,cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl, O-phenyl, O-pyridyl and

 and n is 0, 1, 2, or 3; R⁴ is selected from: H, F, CH₃ and CH₂CH₃;R^(5a) is H or CH₃; and R^(5b) is H or CH₃; or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. 28.A pharmaceutical composition comprising: (A) a therapeutically effectiveamount of at least one compound of claim 1, or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; and(B) at least one pharmaceutically acceptable excipient.
 29. (canceled)30. A method of treating a subject suffering from or diagnosed with adisease, disorder, or condition mediated by MGL receptor activity,comprising administering to a subject in need of such treatment atherapeutically effective amount of at least one compound gf claim 1, ora pharmaceutically acceptable salt, isotope, N-oxide, solvate, orstereoisomer thereof, optionally wherein the MGL receptor mediateddisease, disorder or condition is selected from: (a) pain, psychiatricconditions, neurological conditions, cancers, and eye conditions; (b)major depressive disorder, treatment-resistant depression, anxiousdepression, autism spectrum disorders, Asperger syndrome, and bipolardisorder; and (c) inflammatory pain. 31-33. (canceled)